Macrocyclic quinazoline derivatives as antiproliferative agents

ABSTRACT

The present invention concerns the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents O, CH 2 , NH or S; in particular Z represents NH; Y represents —C 3-9 alkyl-, —C 3-9 alkenyl-, —C 3-9 alkynyl-, —C 3-7 alkyl-CO—NH— optionally substituted with amino, mono- or di(C 1-4 alkyl)amino or C 1-4  alkyloxycarbonylamino-, —C 3-7 alkenyl-CO—NH— optionally substituted with amino, mono- or di(C 1-4 alkyl)amino- or C 1-4 alkyloxycarbonylamino-, C 1-5 alkyl-oxy-C 1-5 alkyl-, —C 1-5 alkyl NR 13 —, —C 1-5 alkyl-, —C 1-5 alkyl-NR 14 —CO—C 1-5 alkyl-, —C 1-5 alkyl-CO NR 15 —C 1-5 alkyl-, —C 1-6 alkyl-CO—NH—, —C 1-6 alkyl-NH—CO—, —C 1-3 alkyl-NH—CS-Het 20 -, —C 1-3 alkyl-NH—CO-Het 20 , —C 1-2 alkyl-CO-Het 21 -CO—, -Het 22 -CH 2 —CO—NH—C 1-3 alkyl-, —CO—NH—C 1-6 alkyl-, —NH—CO—C 1-6 alkyl-, —CO—C 1-7 alkyl-, —C 1-7 alkyl-CO—, —C 1-6 alkyl-CO—C 1-6 alkyl-, —C 1-2 alkyl-NH—CO—CR 16 R 17 —NH—, —C 1-2 alkyl-CO—NH—CR 18 R 19 —CO—, —C 1-2 alkyl-CO—NR 20 —C 1-3 alkyl-CO—, C 1-2 alkyl-NR 21 —CH 2 —CO—NH—C 1-3 alkyl-, or NR 22 —CO—C 1-3 alkyl-NH—, X 1  represents a direct bond, O or —O—C 1-2 alkyl-, CO, —CO—C 1-2 alkyl-, NR 11 , —NR 11 —C 1-2 alkyl-, —CH 2 —, —O—N═CH— or —C 1-2 alkyl-; X 2  represents a direct bond, O, —O—C 1-2 alkyl-, CO, —CO—C 1-2 alkyl-, NR 12 , —NR 12 —C 1-2 alkyl-, —CH 2 —, —O—N═CH— or —C 1-2 alkyl-. The growth inhibitory effect anti-tumour activity of the present compounds has been demonstrated in vitro, in enzymatic on the receptor tyrosine kinase EGFR.

This invention relates to quinazoline derived macrocycles that have beenfound to possess anti-proliferative activity, such as anti-canceractivity and are accordingly useful in methods of treatment of the humanor animal body, for example in the manufacture of medicaments for use inhyper proliferative disorders such as atherosclerosis, restenosis andcancer. The invention also relates to processes for the manufacture ofsaid quinazoline derivatives, to pharmaceutical compositions containingthem and to their use in the manufacture of medicaments of use in theproduction of anti-proliferative effect.

In particular, the compounds of the present invention were found toinhibit tyrosine kinase enzymes, also called tyrosine kinases. Tyrosinekinases are a class of enzymes, which catalyse the transfer of theterminal phosphate of adenosine triphosphate to the phenolic hydroxylgroup of a tyrosine residue present in the target protein. It is known,that several oncogenes; involved in the transformation of a cell into amalignant tumour cell, encode tyrosine kinase enzymes including certaingrowth factor receptors such as EGF, FGF, IGF-1R, IR, PDGF and VEGF.This family of receptor tyrosine kinases and in particular the EGFfamily of receptor tyrosine kinases are frequently present in commonhuman cancers such as breast cancer, non-small cell lung cancersincluding adenocarcinomas and squamous cell cancer of the lung, bladdercancer, oesophageal cancer, gastrointestinal cancer such as colon,rectal or stomach cancer, cancer of the prostate, leukaemia and ovarian,bronchial or pancreatic cancer, which are examples of cell proliferationdisorders.

Accordingly, it has been recognised that the selective inhibition oftyrosine kinases will be of value in the treatment of cell proliferationrelated disorders. Support for this view is provided by the developmentof Herceptin® (Trastuzumab) and Gleevec™ (imatinib mesylate) the firstexamples of target based cancer drugs. Herceptin® (Trastuzumab) istargeted against Her2/neu, a receptor tyrosine kinase found to beamplified up to 100-fold in about 30% of patients with invasive breastcancer. In clinical trials Herceptin® (Trastuzumab) proved to haveanti-tumour activity against breast cancer (Review by L. K. Shawer etal, “Smart Drugs: Tyrosine kinase inhibitors in cancer therapy”, 2002,Cancer Cell Vol. 1, 117), and accordingly provided the proof ofprinciple for therapy targeted to receptor tyrosine kinases. The secondexample, Gleevec™ (imatinib mesylate), is targeted against the abelsontyrosine kinase (BcR-Abl), a constitutively active cytoplasmic tyrosinekinase present in virtually all patients with chronic myelogenousleukemia (CML) and 15% to 30% of adult patients with acute lymphoblasticleukaemia. In clinical trials Gleevec™ (imatinib mesylate) showed aspectacular efficacy with minimal side effects that led to an approvalwithin 3 months of submission. The speed of passage of this agentthrough clinical trials and regulatory review has become a case study inrapid drug development (Drucker B. J. & Lydon N, “Lessons learned fromthe development of an Abl tyrosine kinase inhibitor for chronicmyelogenous leukaemia.”, 2000, J. Clin. Invest. 105, 3).

Further support is given by the demonstration that EGF receptor tyrosinekinase inhibitors, specifically attenuates the growth in athymic nudemice of transplanted carcinomas such as human mammary carcinoma or humansquamous cell carcinoma (Review by T. R. Burke Jr., Drugs of the Future,1992, 17, 119). As a consequence, there has been considerable interestin the development of drugs to treat different cancers that target theEGFR receptor. For example, several antibodies that bind to theextra-cellular domain of EGFR are undergoing clinical trials, includingErbitux™ (also called C225, Cetuximab), which was developed by ImcloneSystems and is in Phase III clinical trials for the treatment of severalcancers. Also, several promising orally active drugs that are potent andrelatively specific inhibitors of the EGFR tyrosine kinase are now welladvanced in clinical trials. The AstraZeneca compound ZD1839, which isnow called IRESSA® and approved for the treatment of advancednon-small-cell lung cancer, and the OSI/Genentech/Roche compoundOSI-774, which is now called Tarceva™ (erlotinib), have shown markedefficacy against several cancers in human clinical trials (Morin M. J.,“From oncogene to drug: development of small molecule tyrosine kinaseinhibitors as anti-tumour and anti-angiogenic agents, 2000, Oncogene 19,6574).

In addition to the above, EGF receptor tyrosine kinases has been shownto be implicated in non-malignant proliferative disorders such aspsoriasis (Elder et al., Science, 1989, 243; 811). It is thereforeexpected that inhibitors of EGF type receptor tyrosine kinases will beuseful in the treatment of non-malignant diseases of excessive cellularproliferation such as psoriasis, benign prostatic hypertrophy,atherosclerosis and restenosis.

It is disclosed in International Patent Application WO96/33980 and in J.Med. Chem, 2002, 45, 3865 that certain 4 anilino substituted quinazolinederivatives may be useful as inhibitors of tyrosine kinase and inparticular of the EGF type receptor tyrosine kinases. Unexpectedly itwas found that Quinazoline derivatives of the present formula (I) thatare different in structure, show to have tyrosine kinase inhibitoryactivity.

It is accordingly an object of the present invention to provide furthertyrosine kinase inhibitors useful in the manufacture of medicaments inthe treatment of cell proliferative related disorders.

This invention concerns compounds of formula (I)

the N-oxide forms, the pharmaceutically acceptable addition salts andthe stereochemically isomeric forms thereof, wherein

-   Z represents O, CH₂, NH or S; in particular Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₃₋₉alkynyl-,    —C₃₋₇alkyl-CO—NH— optionally substituted with amino, mono- or    di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-,    —C₃₋₇alkenyl-CO—NH— optionally substituted with amino, mono- or    di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-,    —C₃₋₇alkynyl-CO—NH— optionally substituted with amino, mono- or    di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-,    —C₁₋₅alkyl-oxy-C₁₋₅alkyl, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-,    —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—, —C₁₋₃alkyl-NH—CS-Het²⁰-,    —C₁₋₃alkyl-NH—CO-Het²⁰-, C₁₋₂alkyl-CO-Het²¹-CO—,    -Het²²-CH₂—CO—NH—C₁₋₃alkyl-, —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-,    —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO—, —C₁₋₆alkyl-CO—C₁₋₆alkyl-,    —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—,    —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—,    —C₁₋₂alkyl-NR²¹—CH₂—CO—NH—C₁₋₃alkyl-, or —NR²²—CO—C₁₋₃alkyl-NH—;-   X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO— C₁₋₂alkyl-,    NR¹¹, —NR¹¹—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO— C₁₋₂alkyl-,    NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-, halo-phenyl-carbonylamino-,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-,    -   C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono-        or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl, C₁₋₄alkyl-,        C₂₋₆alkynyl-,    -   C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-,        dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R³ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one    or more substituents selected from halo, C₁₋₄alkyloxy-, amino-,    mono- or di(C₁₋₄alkyl)amino-, C₁₋₄alkyl-sulfonyl- or phenyl;-   R⁴ represents hydrogen, hydroxy, Ar³-oxy, Ar⁴—C₁₋₄alkyloxy-,    C₁₋₄alkyloxy-, C₂₋₄alkenyloxy- optionally substituted with Het¹² or    R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from C₁₋₄alkyloxy-, hydroxy, halo,    Het²-, —NR⁷R⁸, -carbonyl- NR⁹R¹⁰ or Het³-carbonyl-;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl,    Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl,    Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-,    Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-;-   R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₄alkyl    C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or    polyhydroxy-C₁₋₄alkyl-;-   R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-,    C₂₋₄alkenylcarbonyl-optionally substituted with    Het⁷-C₁₋₄alkylaminocarbonyl, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-,    Het¹⁸-C₁₋₄alkyl-, phenyl-C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷,    C₂₋₄alkenylcarbonyl- optionally substituted with    Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or R¹² represents phenyl optionally    substituted with one or where possible two or more substituents    selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-;-   R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or    phenyl optionally substituted with one or where possible two or more    substituents selected from hydrogen, hydroxy, amino or    C₁₋₄alkyloxy-;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen,    C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-;-   R¹⁶ and R¹⁷ each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with phenyl, indolyl, methylsulfide, hydroxy,    thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine,    imidazoyl or guanidino;-   R¹⁸ and R¹⁹ each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with phenyl, indolyl, methylsulfide, hydroxy,    thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine,    imidazoyl or guanidino;-   R²⁰ and R²² each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with hydroxy or C₁₋₄alkyloxy;-   R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or R²¹    represents mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-carbonyl-    optionally substituted with hydroxy, pyrimidinyl, dimethylamine or    C₁₋₄alkyloxy;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidiniyl, pyrrolidinyl, thiomorpholinyl or    dithianyl wherein said Het² is optionally substituted with one or    where possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-,    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or    di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-;-   Het³, Het⁴ and Het⁸ each independently represent a heterocycle    selected from morpholinyl, piperazinyl, piperidinyl, furanyl,    pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or    Het⁸ is optionally substituted with one or where possible two or    more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-,    C₃₋₆cycloalkyl-C₁₋₄alkyl-7, aminosulfonyl-, mono- or    di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-;-   Het⁵ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or    -polyhydroxy-C₁₋₄alkyl-;-   Het⁶ and Het⁷ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het⁹ and Het¹⁰ each independently represent a heterocycle selected    from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl,    dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is    optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or    amino-C₁₋₄alkyl-;-   Het¹¹ represents a heterocycle selected from indolyl or-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het¹² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-;-   Het¹³ represent a heterocycle selected from pyrrolidinyl optionally    substituted with one or, where possible two or more substituents    selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-,    C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁴ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-,    C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁵ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl; and-   Het¹⁷ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    -   hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or        polyhydroxy-C₁₋₄alkyl-;-   Het²⁰, Het²¹ and Het²² each independently represent a heterocycle    selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from hydroxy, C₁₋₄alkyl,    hydroxy-C₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-;-   Het²³ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl    optionally substituted with cyano, C₁₋₄alkylsulfonyl-,    C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl,    aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.

As used in the foregoing definitions and hereinafter,

-halo is generic to fluoro, chloro, bromo and iodo;

—C₁₋₂alkyl defines methyl or ethyl;

—C₁₋₃alkyl defines straight and branched chain saturated hydrocarbonradicals having from 1 to 3 carbon atoms such as, for example, methyl,ethyl, propyl and the like;

—C₁₋₄alkyl defines straight and branched chain saturated hydrocarbonradicals having from 1 to 4 carbon atoms such as, for example, methyl,ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyland the like;

—C₁₋₅alkyl defines straight and branched chain saturated hydrocarbonradicals having from 1 to 5 carbon atoms such as, for example, methyl,ethyl, propyl, butyl, pentyl, 1-methylbutyl, 2,2-dimethylpropyl,2,2-dimethylethyl and the like;

—C₁₋₆alkyl is meant to include C₁₋₅alkyl and the higher homologuesthereof having 6 carbon atoms such as, for example hexyl,1,2-dimethylbutyl, 2-methylpentyl and the like;

—C₁₋₇alkyl is meant to include-C₁₋₆alkyl and the higher homologuesthereof having 7 carbon atoms such as, for example 1,2,3-dimethylbutyl,1,2-methylpentyl and the like;

—C₃₋₉alkyl defines straight and branched chain saturated hydrocarbonradicals having from 3 to 9 carbon atoms such as propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl and the like;

—C₂₋₄alkenyl defines straight and branched chain hydrocarbon radicalscontaining one double bond and having from 2 to 4 carbon atoms such as,for example vinyl, 2-propenyl, 3-butenyl, 2-butenyl and the like;

—C₃₋₉alkenyl defines straight and branched chain hydrocarbon radicalscontaining one double bond and having from 3 to 9 carbon atoms such as,for example 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, 3-hexenyl and the like;

—C₂₋₆alkynyl defines straight and branched chain hydrocarbon radicalscontaining one triple bond and having from 2 to 6 carbon atoms such as,for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl,3-methyl-2-butynyl, 3-hexynyl and the like;

—C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl;

—C₁₋₄alkyloxy defines straight or branched saturated hydrocarbonradicals such as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy,2-methylpropyloxy and the like;

—C₁₋₆alkyloxy is meant to include C₁₋₄alkyloxy and the higher homologuessuch as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy,2-methylpropyloxy and the like;

-polyhydroxy-C₁₋₄alkyl is generic to a C₁₋₄alkyl as definedhereinbefore, having two, three or were possible morehydroxy-substituents, such as for example

As used in the foregoing definitions and hereinafter, the term formylrefers to a radical of formula —CH(═O). When X¹ represent the divalentradical —O—N═CH—, said radical is attached with the carbon atom to theR³, R⁴ bearing cyclic moiety of the compounds of formula (I) and when X²represents the divalent radical —N═CH—, said radical is attached withthe carbon atom to the R¹, R² bearing phenyl moiety of the compounds offormula (I).

The heterocycles as mentioned in the above definitions and hereinafter,are meant to include all possible isomeric forms thereof, for instancepyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyland 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 3,4-oxadiazolyl; thiadiazolylincludes 1,2,3-thiadiazolyl,-1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and1,3,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.

Further, the heterocycles as mentioned in the above definitions andhereinafter may be attached to the remainder of the molecule of formula(I) through any ring carbon or heteroatom as appropriate. Thus, forexample, when the heterocycle is imidazolyl, it may be a 1-imidazolyl,2-imidazolyl, 3-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it isthiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when itis triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when itis benzothiazolyl, it may be 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl and 7-benzothiazolyl.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acid. Appropriate acids comprise, for example, inorganicacids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid;sulfuric; nitric; phosphoric and the like acids; or organic acids suchas, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic,oxalic, malonic, succinic (i.e. butane-dioic acid), maleic, fumaric,malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic pamoic and the like acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic base additionsalt forms which the compounds of formula (I) are able to form. Examplesof such base addition salt forms are, for example, the sodium,potassium, calcium salts, and also the salts with pharmaceuticallyacceptable amines such as, for example, ammonia, alkylamines,benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e.g.arginine, lysine.

Conversely said salt forms can be converted by treatment with anappropriate base or acid into the free acid or base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term stereochemically isomeric forms as used hereinbefore definesthe possible different isomeric as well as conformational forms whichthe compounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically and conformationally isomeric forms, saidmixtures containing all diastereomers, enantiomers and/or conformers ofthe basic molecular structure. All stereochemically isomeric forms ofthe compounds of formula (I) both in pure form or in admixture with eachother are intended to be embraced within the scope of the presentinvention.

Some of the compounds of formula (I) may also exist in their tautomericforms.

Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

A first group of compounds according to the present invention consistsof those compounds of formula (I) wherein one or more of the followingrestrictions apply;

-   Z represents O, NH or S;-   Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,    —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—,    —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-, C₁₋₇alkyl-CO—,    —C₁₋₆alkyl-CO—C₁₋₆alkyl-, —C₁₋₂alkyl-NH—CO—CHR¹⁶—NH—;-   X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₇alkyl-,    NR¹¹, —NR¹¹—C₁₋₂alkyl-; —CH₂—, —N═CH— or —C₁₋₂alkyl-;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—O —N═CH— or —C₁₋₂alkyl-;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo;-   R² represents hydrogen, cyano, halo; hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-,    aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl,    C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-,    C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R³ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one    or more substituents selected from halo, C₁₋₄alkyloxy-, amino-,    mono- or di(C₁₋₄alkyl)amino-,    -   C₁₋₄alkyl-sulfonyl- or phenyl;-   R⁴ represents hydrogen, hydroxy, Ar³-oxy, Ar⁴—C₁₋₄alkyloxy-,    C₁₋₄alkyloxy-, C₂₋₄alkenyloxy- optionally substituted with Het¹² or    R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from C₁₋₄alkyloxy-, hydroxy, halo,    Het²-, —NR⁷R⁸, -carbonyl- NR⁹R¹⁰ or Het³-carbonyl-;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl,    Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl,    Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-,    Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-;-   R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₄alkyl,    C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl, C₁₋₄-alkyloxyC₁₋₄alkyl- or    polyhydroxy-C₁₋₄alkyl-;-   R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-,    C₂₋₄alkenylcarbonyl-optionally substituted with    Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷,    Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with    Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or R¹² represents phenyl optionally    substituted with one or where possible two or more substituents    selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-;-   R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or    phenyl optionally substituted with one or where possible two or more    substituents selected from hydrogen, hydroxy, amino or    C₁₋₄alkyloxy-;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen,    C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-;-   R¹⁶ represents hydrogen or C₁₋₄alkyl optionally substituted with    phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl,    aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazoyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-,    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or    di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-;-   Het³, Het⁴ and Het⁸ each independently represent a heterocycle    selected from morpholinyl, piperazinyl, piperidinyl, furanyl,    pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or    Het⁸ is optionally substituted with one or where possible two or    more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-,    C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or    di(C₁₋₄alkyl)aminosulfonyl-   Het⁵ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het⁶ and Het⁷ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het⁹ and Het¹⁰ each independently represent a heterocycle selected    from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl,    dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is    optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or    amino-C₁₋₄alkyl-;-   Het¹¹ represents a heterocycle selected from indolyl or-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het¹² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-;-   Het¹³ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁴ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁵ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl; and-   Het¹⁷ represent a heterocycle selected form pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    -   hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or        polyhydroxy-C₁₋₄alkyl-;-   Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl    optionally substituted with cyano, C₁₋₄alkylsulfonyl-,    C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl,    aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.

An interesting group of compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,    —C₁₋₆alkyl-NH—CO—, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-,    —C₁₋₇alkyl-CO—, C₁₋₆alkyl-CO—C₁₋₆alkyl,    —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁵R¹⁹—CO—,    —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—,    —C₁₋₂alkyl-NR²¹—CH₂—CO—NH—C₁₋₃alkyl-, —NR²²—CO—C₁₋₃alkyl-NH—,    —C₁₋₃alkyl-NH—CO-Het²⁰-, C₁₋₂alkyl-, —O—CO-Het²¹-CO—, or    -Het²²-CH₂—CO—NH—C₁₋₃alkyl-;-   X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or —NR¹¹—C₁₋₂alkyl-;    in a particular embodiment X¹ represents —NR¹¹—, —O— or —O—CH₂—;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹² or    NR¹²—C_(—) ₂alkyl-; in a particular embodiment X² represents a    direct bond, —C₁₋₂alkyl-, —O—C₁₋₂alkyl, —O— or —O—CH₂—;-   R¹ represents hydrogen, cyano, halo or hydroxy, preferably halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-,    Ar⁵ or Het¹;    -   In a further embodiment R² represents hydrogen, cyano, halo,        hydroxy, C₂₋₆alkynyl- or Het¹; in particular R² represents        hydrogen, cyano, halo, hydroxy, or Ar⁵;-   R³ represents hydrogen;-   R⁴, represents hydrogen, hydroxy, —C₁₋₄alkyloxy- or R⁴ represents    C₁₋₄alkyloxy substituted with one or where possible two or more    substituents selected from C₁₋₄alkyloxy- or Het²-;-   R¹² represents hydrogen, C₁₋₄alkyl- or —C₁₋₄alkyl-oxy-carbonyl-;-   R¹³ represents hydrogen or Het⁴-C₁₋₄alkyl, in particular    morpholinyl-C₁₋₄alkyl;-   R¹⁴ and R¹⁵ represents hydrogen;-   R¹⁶ represents hydrogen or C₁₋₄alkyl substituted with hydroxy,-   R¹⁷ represents hydrogen or C₁₋₄alkyl, in particular hydrogen or    methyl;-   R¹⁹ represents hydrogen or C₁₋₄alkyl optionally substituted with    hydroxy or phenyl;-   R¹⁹ represents hydrogen or C₁₋₄alkyl, in particular hydrogen or    methyl, even more particular hydrogen;-   R²⁰ represents hydrogen or C₁₋₄alkyl, in particular hydrogen or    methyl;-   R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or R²¹    represents mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-carbonyl-    optionally substituted with hydroxy, pyrimidinyl, dimethylamine or    C₁₋₄alkyloxy;-   R²² represents hydrogen or C₁₋₄alkyl optionally substituted with    hydroxy or C₁₋₄alkyloxy;-   Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-; In a    further embodiment Het² represents a heterocycle selected from    morpholinyl or piperidinyl optionally substituted with C₁₋₄alkyl-,    preferably methyl;-   Het³ represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het³ is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   Het¹⁶ represents a heterocycle selected from piperidinyl or    pyrrolidinyl;-   Het²⁰ represents pyrrolidinyl, 2-pyrrolidinonyl, piperidinyl or    hydroxy-pyrrolidin yl; preferably pyrrolidinyl or    hydroxy-pyrrolidinyl;-   Het²¹ represents pyrrolidinyl or hydroxy-pyrrolidinyl;-   Het²² represents pyrrolidinyl piperazinyl or piperidinyl.

A particular group of compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply.

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₃₋₇alkyl-CO—NH optionally    substituted with amino, mono- or di(C₁₋₄alkyl)amino or    C₁₋₄alkyloxycarbonylamino-, —C₃₋₇alkenyl-CO—NH— optionally    substituted with amino, mono- or di(C₁₋₄alkyl)amino- or    C₁₋₄alkyloxycarbonylamino-, C₁₋₅alkyl-NR¹³C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₅alkyl-CO    NR¹⁵—C₁₋₅alkyl-, —C₁₋₃alkyl-NH—CO-Het²⁰-, —C₁₋₂alkyl-CO-Het²¹-CO—,    C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁵R¹⁹—CO—,    —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—, or —NR²²—CO—C₁₋₃alkyl-NH—;    -   even more particular Y represents —C₃₋₉alkyl-,        —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,        —C₁₋₃alkyl-NH—CO-Het²⁰-, —C₁₋₂alkyl-CO-Het²¹-CO—, or        —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—;-   X¹ represents a direct bond, O, or —O—C₁₋₂alkyl-;-   X² represents a direct bond, —CO—C₁₋₂alkyl-, NR¹², —NR¹²—C₁₋₂alkyl-,    —O—N═CH— or —C₁₋₂alkyl-; even more particular X² represents    —CO—C₁₋₂alkyl- or NR¹²—C₁₋₂alkyl-;-   R¹ represents hydrogen or halo, preferably hydrogen, chloro, fluoro    or bromo;-   R² represents hydrogen or halo, preferably hydrogen, chloro, fluoro    or bromo;-   R³ represents hydrogen;-   R⁴ represents hydrogen or C₁₋₄alkyloxy, preferably C₁₋₄alkyloxy,    even more preferably methoxy;-   R¹² represents hydrogen or C₁₋₄alkyl, preferably hydrogen or methyl;-   R¹³ represents hydrogen or C₁₋₄alkyl;-   R¹⁴ represents hydrogen;-   R¹⁵ represents hydrogen;-   R¹⁶ and R¹⁷ each independently represent hydrogen or C₁₋₄alkyl;-   R¹⁸ and R¹⁹ each independently represent hydrogen or C₁₋₄alkyl    optionally substituted with phenyl or hydroxy;-   R²⁰ and R²¹ each independently represent hydrogen or C₁₋₄alkyl    optionally substituted with C₁₋₄alkyloxy;-   Het²⁰, Het²¹ and Het²² each independently represent a heterocycle    selected from the group consisting pyrrolidinyl, 2-pyrrolidinonyl or    piperidinyl optionally substituted with hydroxy.

A preferred group of compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO—, —CO—C₁₋₇alkyl-,    —C₁₋₇alkyl-CO— or C₁₋₆alkyl-CO—C₁₋₆alkyl; alkyl-NH—CO-Het²⁰-,    C₁₋₂alkyl-CO-Het²¹-CO—, —C₁₋₂alkyl-NH—CO—CR¹⁶R₁₇—NH—,    —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—, —C₁₋₂alkyl-CO—NR²⁰—C-   X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or —NR¹¹—C₁₋₂alkyl-;    in a particular embodiment X¹ represents NR¹¹—, —O— or —O—CH₂—;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹² or    NR¹²—C₁₋₂alkyl-; in a particular embodiment X² represents a direct    bond, —C₁₋₂alkyl-, —O—C₁₋₂alkyl, —O— or —O—CH₂—;-   R¹ represents hydrogen, cyano, halo or hydroxy, preferably halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-,    Ar⁵ or Het¹; In a further embodiment R² represents hydrogen, -cyano,    halo, hydroxy, C₂₋₆alkynyl- or Het¹; in particular R² represents    hydrogen, cyano, halo, hydroxy, or Ar⁵;-   R³ represents hydrogen;-   R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy- or R⁴ represents    C₁₋₄alkyloxy substituted with one or where possible two or more    substituents selected from C₁₋₄alkyloxy- or Het²-;-   R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   R¹³ represents Het¹⁴—C₁₋₄alkyl, in particular morpholinyl-C₁₋₄alkyl;-   Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-; In a    further embodiment Het² represents a heterocycle selected from    morpholinyl or piperidinyl optionally substituted with C₁₋₄alkyl-,    preferably methyl;-   Het³ represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het³ is    optionally substituted with one or where possible two or mote    substituents selected from hydroxy, amino or C₁₋₄alkyl;-   Het¹⁶ represents a heterocycle selected from piperidinyl or    pyrrolidinyl.

A further group of compounds consists of those compounds of formula (I)wherein one or more of the following restrictions apply:

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-,    —C₁₋₆alkyl-NH—CO—, —CO—C₁₋₇alkyl- or —C₁₋₇alkyl-CO—;-   X¹ represents —NR¹¹, —O— or —O—CH₂—;-   X² represents a direct bond, —NR¹², —NR¹²—C₁₋₂alkyl-, —CO—, —O— or    —O—CH₂—;-   R¹ represents halo; in particular R¹ represents chloro, fluoro or    bromo and is at position 5′;-   R² represents hydrogen, cyano, halo, hydroxy, or Ar⁵;-   R³ represents hydrogen;-   R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from C₁₋₄alkyloxy- or Het²-;-   R¹² represents C₁₋₄alkyl or R¹² represents C₁₋₄alkyl-oxy-carbonyl;    —R¹³ represents Het¹⁴-C₁₋₄alkyl;-   Het² represents a heterocycle selected from morpholinyl or    piperidinyl optionally substituted with C₁₋₄alkyl-;-   Het³ represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het³ is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄-alkyl-;-   Het¹⁴ represents morpholinyl.

In a further embodiment of the present invention the compounds offormula (I) are selected from the group consisting of;

-   4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine,    17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine,    17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl-benzamide,    4-fluoro-N-(8,9,10,11,12,13-hexahydro-20-methoxy-4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecin-16-yl)--   4,6-ethanediylidene-8H,14H-pyrimido[4,5-b][6,12,1]benzodioxaazacylohexadecine,    18-chloro-9,10,11,12,15,20--hexahydro-21-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,11]benzoxadiazacyclohexadecin-11(12H)-one,    18-chloro-9,10,13,14,15,20-hexahydro-21-methoxy--   4,6-ethanediylidene-14H-pyrimido[4,5-b][6,9,12,1]benzotrioxaazacyclohexadecine,    18-chloro-8,9,11,12,15,20-hexahydro-21-methoxy--   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    19-chloro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-[(8H)-one,    17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy-13-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy--   4,6-ethanediylidenepyrimido-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-14-methyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,13]benzoxatriazacyclohexadecin-11(12H)-one,    18-chloro-9,10,13,14,15,20-hexahydro-21-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,10,14]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy--   4,6-ethenopyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    17-chloro-10,11,14,19-tetrahydro-20-methoxy--   4,6-etheno-8H-pyrimido[4,5-b]pyrrolo[2,1-1][6,1,10,13]benzoxatriazacyclohexadecine-12,15(14H)-dione,    20-chloro-9,10,11,12a,13,17,22-heptahydro-23-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-1][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    20-chloro-8,9,10,11,12a,13,14,15,17,22-decahydro-23-methoxy--   4,6-ethenopyrmido[4,5-b][6,1,9,14]benzoxatriazacycloheptadecine-9,14(8H,15H)-dione,    19-chloro-10,11,12,13,16,21-hexahydro-22-methoxy--   4,6-etheno-8H-pyrimido[4,5-b][6,1,9,13]benzoxatriazacyclohexadecine--9,13(10,11,14H)-dione,    18-chloro-11,12,15,20-tetrahydro-21-methoxy--   4,6-ethenopyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione,    9-chloro-9,10,12,13,16,21-hexahydro-22-methoxy--   4,6-ethenopyrimido[4,5-b][6,1,11,16]benzoxatriazacyclononadecine-11,16(8H,17H)-dione,    21-chloro-9,10,12,13,14,15,18,23-octahydro-24-methoxy--   4,6-etheno-8H-pyrimido[4,5-b]6,1,11,15]benzoxatriazacyclooctadecine-11,15(12H,16H)-dione,    20-chloro-9,10,13,14,17,22-hexahydro-23-methoxy--   4,6-ethenopyimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine,    17-bromo-16-fluoro-8,9,10,11,12,13,14,19-octahydro-20-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    17-chloro-10,11,14,19-tetrahydro-20-methoxy-11-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    17-chloro-10,11,14,19-tetrahydro-20-methoxy-11-(1-methylethyl)--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    11-chloro-10,11,14,19-tetrahydro-20-methoxy-11-(phenylmethyl))--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,    18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-12-(1-methylethyl)--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine    11,14-dione,    18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-12,12-dimethyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,    18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-12-(2-methylpropyl)--   4,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine-12,15-dione,    19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-13-(2-methylpropyl)--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,    18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine-12,15-dione,    19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    10,11,14,19-tetrahydro-20-methoxy-11-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    10,11,14,19 tetrahydro-20-methoxy- (1-methylpropyl)--   9,11-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclopentadecine-14,19(5H,13H)-dione,    16,17,18,18a,20,21-hexahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    10,11,14,19-tetrahydro-20-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,13]benzoxatriazacyclohexadecine-9,13(10H,14H)-dione,-11,12,15,20-tetrahydro-21-methoxy-,-   4,6-ethanediylidenepytimido[4,5-b][6,1,9,14]benzoxatriazacycloheptadecine-9,14(8H,15H)-dione,    10,11,12,13,16,21-hexahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    19-chloro-18-fluoro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecine,    18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxy-14-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-11(8H)-one,    17-chloro-16-fluoro-9,10,12,13,14,19-hexahydro-20-methoxy-13-methyl--   4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-14-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    17-chloro-16-fluoro-9,10,12,13,14,19-hexahydro-20-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-21-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy--   9,11-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclopentadecine-14,19(5H,13H)-dione,    3-chloro-16,17,18,18a,20,21-hexahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    17-chloro-10,11,14,19-tetrahydro-20-methoxy-10-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    17-chloro-10,11,14,19-tetrahydro-11-(1-hydroxyethyl)-20-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,    15E)-dione,    19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-(1-methylpropyl)--   4,6-ethanediylidenepyramido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    17-chloro-10,11,14,19-tetrahydro-11-(hydroxymethyl)-20-methoxy--   4,6-ethanediylidenepyrimido[4,5][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione,    19-chloro-9,10,12,13,16,21-hexahydro-13-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,    15H)-dione,    19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-methyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,    18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,14]benzoxatriazacyclooctadecine-9,14-dione,    20-chloro-10,11,12,13,15,16,17,22-octahydro-23-methoxy--   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    19-chloro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-1][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    20-chloro-8,9,10,11,12a,13,14,15,17,22-decahydro-23-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-1][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    20-chloro-19-fluoro-8,9,10,11,12a,13,14,15,17,22-decahydro-23-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-10-ethyl-8,9,10,11,14,15,16,21-octahydro-22-methoxy--   1,22-ethanediylidene-5H,17H-pyrimido[4,5-b]pyrrolo[2,1-h][6,1,9,12]benzoxatriazacycloheptadecin-14(15H)-one,    7-chloro-10,11,12,13,18,19,19a,20-octahydro-24-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclooctadecin-13(14H)-one,    20-chloro-9,10,11,12,15,16,17,22-octahydro-23-methoxy--   14H-4,6-ethanediylidene-9,13-methano-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacycloeicosin-15(16H)-one,    22-chloro-9,10,11,12,17,18,19,24-octahydro-26-methoxy--   13H-4,6-ethanediylidene-9,12-ethanopyrimido[4,5-b][6,1,11,14]benzoxatriazacyclononadecin-14(15H)-one,    21-chloro-8,9,10,11,16,17,18,23-octahydro-26-methoxy--   14H-4,6-ethanediylidene-10,13-ethano-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacycloeicosin-15(16H)-one,    22-chloro-9,10,11,12,17,18,19,24-octahydro-27-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]acetyl]-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin--   12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[2-(hydroxymethyl)-4-morpholinyl]acetyl]-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[(2-hydroxyethyl)methylamino]acetyl]-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[[[2-(4-pyridinyl)ethyl]amino]acetyl]--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-10-[[[2-(dimethylamino)ethyl]methylamino]acetyl]-8,9,10,11,14,15,16,21-octahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[[(2-methoxyethyl)amino]acetyl]--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[[(3-methoxypropyl)amino]acetyl]--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-(4-morpholinylacetyl)--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,    19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[(4-methyl-1-piperazinyl)acetyl]--   4,6-ethenopyrimido[4,5-b][6,1,2]benzoxadiazacyclopentadecine-13(8H)-carboxylic    acid, 17-bromo-9,10,11,12,14,19-hexahydro-20-methoxy-, phenylmethyl    ester-   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-m][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    21-chloro-9,10,11,12,13a,14,15,16,18,23-decahydro-24-methoxy--   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-2,1-m][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    21-chloro-20-fluoro-9,10,11,12,13a,14,15,16,18,23-decahydro-24-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,16]benzoxadiazacyclononadecin-16(17H)-one,    21-chloro-8,9,10,13,14,15,18,23-octahydro-24-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,16]benzoxadiazacyclononadecin-16(17H)    -one, 21-chloro-8,9,10,13,14,15,18,23-octahydro-24-methoxy--   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecine-11(8H)-thione,    19-chloro-18-fluoro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine,    19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxy-15-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine,    17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,    17-chloro-10,11,14,19-tetrahydro-20-methoxy-11,11-dimethyl--   9,11-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclopentadecine-14,19(5H,13H)-dione,    3-chloro-16,17,18,18a,20,21-hexahydro-17-hydroxy-22-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-15(16H)-one,    20-chloro-9,12,13,14,17,22-hexahydro-23-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine,    20-chloro-9,10,11,12,13,14,15,16,17,22-decahydro-23-methoxy-16-methyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,    18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-10-(2-methoxyethyl)--   4,6-ethanediylidenepyrimido[4,5-b][6,1,12,16]benzoxatriazacyclononadecine-12,16(13H,17H)-dione,    21-chloro-8,9,10,11,14,15,18,23-octahydro-24-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,17]benzoxatriazacycloeicosine-12,17(18H)-dione,    22-chloro-9,10,11,13,14,15,16,19,24-nonahydro-25-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b]pyrrolo[1,2-1][6,1,12,15]benzoxatriazacyclooctadecine-12,17(18)-dione,    22-chloro--9,10,11,14,15,16a,19,24-nonahydro-25-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,    18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy-11,11-dimethyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b]pyrrolo[1,2-1][6,1,12,15]benzoxatriazacyclooctadecine-12,17(18H)-dione,    22-chloro-9,10,11,14,15,16,16a,19,24-nonahydro-15-hydroxy-25-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione,    20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-13-methyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione,    20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14(2-methylpropyl)--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione,    20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14,14-dimethyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriacycyclooctadecine-12,15(16H)-dione,    20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14(phenylmethyl)--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione,    20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14-methyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,    18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy-11-methyl--   1,21-ethanediylidene-5H-pyrimido[4,5-b]pyrrolo[1,2i][6,1,9,12]benzoxatriazacyclohexadecine-13,18(19H)-dione,    7-chloro-10,11,12,13a,14,15,16-heptahydro-23-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,    18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy-10-methyl--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,    18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy-11-(2-methylpropyl)--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,    18-chloro-10,11,13,14,15,20-hexahydro-11-(1-hydroxyethyl)-21-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine    -11,14(8H,15H)-dione,    19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-(2-methylpropyl)-4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione,    19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13,13-dimethyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,    5H)-dione,    19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-(phenylmethyl)--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione,    19-chloro-9,10,12,13,16,21-hexahydro-13-(1-hydroxyethyl)-22-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione,    20-chloro-9,10,11,13,14,17,22-heptahydro-14-(1-hydroxyethyl)-23-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,    18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-10-[2-(4-morpholinyl)ethyl]--   carbamic acid,    (20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxy-15-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-14-yl)-,    1,1-dimethylethyl ester-   carbamic acid,    (20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxy-15-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-14-yl)-,    1,1-dimethylethyl ester-   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,    18-chloro-10,11,13,14,15,20-hexahydro-11-(hydroxymethyl)-21-methoxy--   1,21-ethanediylidene-5H-pyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclohexadecine-13,18(19H)-dione,    7-chloro-10,11,12,13a,14,15,16-heptahydro-15-hydroxy-23-methoxy--   carbamic acid,    (20-chloro-9,10,11,12,13,14,15,16,17,22-decahydro-23-methoxy-15-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-14-yl)-,    1,1-dimethylethyl ester-   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-15(16H)-one,    14-amino-20-chloro-9,10,11,12,13,14,17,22-octahydro-23-methoxy--   carbamic acid,    (18-chloro-11,12,13,14,15,20-hexahydro-21-methoxy-13-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,13]benzoxadiazacyclohexadecin-12-yl)-,    1,1-dimethylethyl ester-   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    19-chloro-9,10,11a,12,13,14,16,21-octahydro-13-hydroxy-22-methoxy--   4,6-ethanediylidene-13,16-ethano-8H-pyrimido[4,5-    b][6,1,9,12,15]benzoxatetraazacyclooctadecin-11(12H)-one,    20-chloro-9,10,14,15,17,22-hexahydro-25-methoxy--   8H-4,6-ethanediylidene-12,15-ethanopyrimido[4,5-b][6,1,9,14]benzoxatriazacycloheptadecin-11(12H)-one,    19-chloro-9,10,13,14,16,21-hexahydro-24-methoxy--   4,6-ethanediylidene-12,16-methano-6H-pyrimido[4,5-b][6,1,9,15]benzoxatriazacyclooctadecin-11(8H)-one,    20-chloro-9,10,12,13,14,15,17,22-octahydro-24-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxatriazacyclopentadecin-11(8H)-one,    17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy-12,13-dimethyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    17-chloro-13-ethyl-9,10,12,13,14,19-hexahydro-20-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    17-chloro-9,10,12,13,14,19-hexahydro-12-(hydroxymethyl)-20-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-1][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    20-chloro-8,9,10,11,12a,13,14,15,17,22-decahydro-14-hydroxy-23-methoxy--   4,6-ethanediylidene-14,17-ethanopyrimido[4,5-b][6,1,10,13,16]benzoxatetraazacyclononadecin-12(13H)-one,    21-chloro-8,9,10,11,15,16,18,23-octahydro-26-methoxy--   4,6-ethanediylidene-13,16-ethano-6H-pyrimido[4,5-b][6,1,10,15]benzoxatriazacyclooctadecin-12(13H)-one,    20-chloro-8,9,10,11,14,15,17,22-octahydro-25-methoxy--   12H-4,6-ethanediylidene-13,17-methanopyrimido[4,5-b][6,1,10,16]benzoxatriazacyclononadecin-12-one,    21-chloro-8,9,10,11,13,14,15,16,18,23-decahydro-25-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-13,14-dimethyl--   4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-14-ethyl-8,9,10,11,13,14,15,20-octahydro-21-methoxy--   4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-8,9,10,11,13,14,15,20-octahydro-13-(hydroxymethyl)-21-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    19-chloro-15-ethyl-9,10,11,12,14,15,16,21-octahydro-22-methoxy--   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxy-14,15-dimethyl--   4,6-ethanediylidenepyrimido[4,5-b][6,1,16]benzoxadiazacyclononadecin-16(17H)-one,    21-chloro-8,9,10,11,12,13,14,15,18,23-decahydro-24-methoxy--   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-15(16H)-one,    20-chloro-14-(dimethylamino)-9,10,11,12,13,14,17,22-octahydro-23-methoxy-

In a particular embodiment of the present invention the compounds offormula (I) are selected from the group consisting of;

-   4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine,    17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl,-   4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine,    17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-,-   4,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine-12,15-dione,    19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-13-(2-methylpropyl)-,-   4,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine-12,15-dione,    19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-,-   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one,    19-chloro-18-fluoro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy-,-   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecine,-   18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxy-14-methyl-,-   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine,    19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxy-15-methyl-,-   4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine,    17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl-,-   12H-4,6-ethanediylidene-13,17-methanopyrimido[4,5-b][6,1,10,16]benzoxatriazacyclononadecin-12-one,    21-chloro-8,9,10,11,13,14,15,16,18,23-decahydro-25-methoxy-,-   4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one,    18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-13,14-dimethyl-,-   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    19-chloro-15-ethyl-9,10,11,12,14,15,16,21-octahydro-22-methoxy-, or-   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]-13(8H)->one,    19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxy-14,15-dimethyl-

Other special group of compounds are:

-   -   those compounds of formula (I) wherein —X¹— represents —O—;    -   those compounds of formula (I) wherein —X¹— represents —NR¹¹—,        in particular —NH—;    -   those compounds of formula (I) wherein R¹ is fluoro, chloro or        bromo;    -   those compounds of formula (I) wherein R² is fluoro, chloro or        bromo;    -   those compounds of formula (I) wherein R² is Het¹, in particular        thiazolyl optionally substituted with methyl;    -   those compounds of formula (I) wherein R² is C₂₋₆alkynyl-, in        particular ethynyl;    -   those compounds of formula (I) wherein R² is Ar⁵, in particular        phenyl optionally substituted with cyano;    -   those compounds of formula (I) wherein R⁴ represents methoxy and        wherein said methoxy is at position 7 of the structure of        formula (I).    -   those compounds of formula (I) wherein R⁴ represents        C₁₋₄alkyloxy substituted with one substituent selected from        C₁₋₄alkyloxy- or Het²-, in particular propyloxy substituted with        morpholinyl;    -   those compounds of formula (I) wherein R¹² is hydrogen or        C₁₋₄alkyl-, in particular methyl or wherein R¹² is        C₁₋₄alkyl-oxy-carbonyl-, in particular t-butyl-oxy-carbonyl-    -   those compounds of formula a) wherein Het² represent morpholinyl        optionally substituted with C₁₋₄alkyl, preferably morpholinyl        attached through the nitrogen atom to the remainder of the        compounds of formula (I);    -   those compounds of formula (I) with Het³ represent morpholinyl        optionally substituted with C₁₋₄alkyl, preferably morpholinyl        attached through the nitrogen atom to the remainder of the        compounds of formula (I);    -   those compounds of formula (I) wherein Het¹² represent        morpholinyl optionally substituted with C₁₋₄alkyl, preferably        morpholinyl attached through the nitrogen atom to the remainder        of the compounds of formula (I).

In a further embodiment of the present invention the X² substituent isat position 2, the R¹ substituent represents hydrogen or halo and is atposition 4′, the R² substituent represents halo and is at position 5′,the R³ substituent is at position 2 and the R⁴ substituent at position 7of the structure of formula (I). Alternatively, the X² substituent is atposition 3′, the R substituent represents hydrogen or halo and is atposition 4′, the R² substituent represents halo and is at position 5′,the R³ substituent is at position 2 and the R⁴ substituent at position 7of the structure of formula (I).

The compounds of this invention can be prepared by any of severalstandard synthetic processes commonly used by those skilled in the artof organic chemistry and described for instance in the followingreferences; “Heterocyclic Compounds”—Vol. 24 (part 4) p 261-304 Fusedpyrimidines, Wiley—Interscience; Chem. Pharm. Bull., Vol. 41(2) 362-368(1993); J. Chem. Soc., Perkin Trans. 1, 2001, 130-137.

As further exemplified in the experimental part of the description, aparticular group of compounds are those compounds of formula (I) were—X¹— represents —O—, hereinafter referred to as compounds of formula(I′) which are generally prepared using the following synthesis scheme.The compounds of this invention may be prepared starting from the known6-acetoxy-4-chloro-7-methoxy quinazoline (II′) or from6-acetoxy-7-benzyloxy-4-chloroquinazoline (II^(a)), which can beprepared from commercially available veratric acid and4-hydroxy-3-methoxy benzoic acid, respectively.

Coupling of the latter compounds with suitable substituted anilines(III′) under standard conditions, for example stirred in propanol at anelevated temperature ranging form 40-100° C. during 3-12 h, anilineswhich in their turn can be prepared according to reaction schemes 4-8,furnish the intermediate compounds (IV′, IV^(a)) (Scheme 1).

Deprotection of the intermediates of formula (IV′-IV^(a)) as describedin Protective Groups in Organic Synthesis by T. W. Greene and P. G. M.Wuts, 3^(rd) edition, 1998 followed by ring closure under Mitsunobuconditions give the target compounds (I′-I′a). (Scheme 2—wherein V andR¹⁶ are defined as hereinbefore)

Alternatively, those compounds of formula (I′^(b)) wherein Y represents—C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,—C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—C₁₋₆alkyl-CO—,—C₁₋₃alkyl-NH—CO-Het²⁰-, -Het²²-CH₂—CO—NH—C₁₋₃alkyl-,—C₁₋₂alkyl-NH—CO—CR¹⁶R⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—,—C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—, —C₁₋₂alkyl-NR²¹—CH₂—CO—NH—C₁₋₃alkyl-or —NR²²—CO—C₁₋₃alkyl-NH— are prepared using the following synthesisscheme. The intermediates of formula (IV^(b)) are obtained as describedhereinbefore. Deprotection and subsequent formation of the correspondingether using the appropriate aminated alcohol under standard conditionsprovides the intermediates of formula (XXVIII). Deprotection followed byring closure provides the target compounds of formula (I′^(b))

More specific examples for the synthesis of compounds of formula(I′^(b)) are provided in reaction schemes 9-12.

For those compounds where X² represents —O—, the suitable substitutedanilines of formula (III^(a)) are generally prepared from thecommercially available nitro-phenols (X) and the α, ω-protectedhalogenated alcohols (XI) under alkaline conditions in a reaction inertsolvent, for example, using dimethylacetamide (DMA) in the presence ofK₂CO₃. The resulting nitro-phenyl derivative (XII) is subsequentlyreduced according to standard conditions, for example, using iron/aceticacid, to yield the substituted anilines of formula (III^(a)) (Scheme 4).

For those compounds where X² represents —NR¹²—C₁₋₂alkyl-, the suitablesubstituted anilines of formula (III^(b)) are generally prepared fromthe commercially available 2-nitro-benzaldehydes (XIII) and the aminesubstituted alcohols (XIV) by reductive amination under standardconditions, for example using NaBH₄ and titanium(iv)isopropoxide asreducing agents in ethanol as solvent, yielding in a first step thenitro-benzylamines of formula (XV).

Next the primary free alcohol is protected using art known procedures,for example, using an esterification reaction with acetic anhydride inthe presence of pyridine.

The thus obtained intermediate of formula (XVI) is subsequently reducedaccording to standard conditions, for example, using hydrogenolysis (H₂,Pt/C, thiophene, MeOH) or tin(II)chloride (SnCl₂, H₂O, EtOH) to yieldthe substituted anilines of formula (III^(b)) (Scheme 5).

Using the aforementioned method in two alternative forms,4-chloro-2-nitrobenzaldehyde has been converted in suitable substitutedanilines of formula (III^(b)). In a first method (Scheme 5a) thesuitable substituted anilines of formula (III^(b)) were obtained byreductive amination of 4-chloro-2-nitrobenzaldehyde with primary aminoacids.

A methanolic solution of 10 mmol aldehyde 1, 20 mmol amino acid 2, 19mmol KF, 1 mL 4% thiophene (in DIPE) and 1 g Pt/C (slurry in THF orMeOH) under 1 atm of hydrogen is stirred at 50° C. (scheme 5a). Thereaction mixture is filtered after consumption of 4 equivalents ofhydrogen (typically after 48 h) and 3 equivalents of Boc anhydride areadded. Next, the solution is stirred for 1-3 h at room temperature (LCMSmonitoring), then an excess of 6 N ammonia in MeOH is added, andstirring is continued for 1 h to work-up excess Boc anhydride. Finally,the solution 1 is evaporated to dryness (sublimation of tert-butylcarbamate is observed) and the resulting Boc-protected N-benzyl aminoacid 4 is purified by HPLC. When R′ is not equal to hydrogen,Boc-protected aniline 5 is observed as the major product. In this casemethod B can be employed to obtain the aniline of type 4 (vide infra).

A second method to obtain the suitable substituted anilines of formula(III^(b)) has been the reductive amination of primary and secondaryamino acids, amino acid hydrochlorides, N-methylallylamine andmethylaminoacetaldehyde dimethyl acetal with4-chloro-2-nitrobenzaldehyde 1 and 4-chloro-3-fluoro-2-nitrobenzaldehyde6 (Scheme 5b). Overall yields vary between 13 and 100%.

To a solution (suspension) of 5 mmol amine 7, 5 mmol aldehyde 1 or 6 in30 mL dichloromethane is added 5 mmol titanium(IV)tert-butoxide and 5mmol DIPEA (when 7 is hydrochloride).¹ After stirring for 15 min, 12mmol sodium triacetoxyborohydride is added and stirring is continued for1-5 h (LCMS monitoring). Next, the reaction is worked up with 10-20 mLof a saturated NaHCO₃-solution and stirring is continued until bubblingstops. The resulting emulsion is filtered over a P3 sintered glassfilter and washed with dichloromethane. The organic layer is separatedand the aqueous phase extracted with dichloromethane. Drying of thecombined organic layers with magnesium sulfate (or potassium carbonate),followed by filtration and evaporation of the solvent yields the crudeN-benzylamine 8, which is usually pure enough to use for the nextreaction step.¹With Ti(IV)isopropoxide, transesferification was observed once when 7was an amino acid tBu ester. The reduction was unexpectedly exothermicin this case, and the heat may have caused this side reaction.

When R is hydrogen, the secondary amine can be protected with a Boc orCbz, group by respectively adding three equivalents of Boc anhydride orbenzyl chloroformate and three eq of DIPEA to a methylene chloridesolution of the amine and stirring for 16-24 h at room temperature. WhenR′ is bulky, Boc protection is generally slow and requires prolongedrefluxing in methylene chloride. Next, excess protecting agent is workedup by adding 6 N ammonia in methanol and stirring for 1 h at roomtemperature. After evaporation of the solvent, the product is purifiedby RP HPLC.

The thus obtained benzylamine 8 is subsequently reduced either byhydrogenolysis or in case R′ contains a double bond by reduction withtin(II)chloride

Nitro Reduction by Hydrogenolysis

The benzylamine 8 is dissolved in methanol (or ethyl acetate or THF)and, upon addition of 1 g Pt/C (slurry in EtOAc) and thiophene (1 mL 4%in DIPE), stirred under 1 atm hydrogen at 50° C. (scheme. 3, step a).After consumption of three equivalents of hydrogen, the mixture isfiltered over dicalite. Removal of the solvent yields the crude aniline9 which, depending on the nature and purity, can be crystallized fromheptane, purified by HPLC or used as a crude in the next reaction step.

Nitro Reduction with tin(II)chloride

This method was used when R′ contains a double bond and hence cannot bereduced hydrogenolytically.

To an ethanolic solution of crude nitro compound 8 is added 5 eq oftin(II)chloride dihydrate (scheme 3, step b). This mixture is stirredfor 1.5 h at 50° C. Next, the solution is cooled to RT, and saturatedsodium bicarbonate and methylene chloride are added (bubbling). Theresulting emulsion is filtered over a P3 sintered glass filter.Separation of the organic layer, followed by drying on anhydrouspotassium carbonate, filtering and removal of the solvent yields thecrude aniline 9, which is usually pure enough to be used in the nextreaction step.

For those compounds where X² represents —O—N═CH—, the suitablesubstituted anilines of formula (III^(c)) are generally preparedaccording to reaction scheme 6.

In a first step the known 2-nitro-benzaldehydes (X) are converted intothe corresponding oxime (XVII) using, for example, the art knowncondensation reaction with hydroxylamine.

Next said oxime of formula XVII is allowed to react with an halogenatedalkylacetate under alkaline conditions, for example using K₂CO₃ in DMSO,followed by reducing the nitro group, for example, with hydrogenolysis(H₂, Pt/C, thiophene, MeOH) or tin(II)chloride (SnCl₂.H₂O, EtOH), toprovide the suitable substituted aniline of formula (III^(c)).

For those compounds where X² represents a direct bond and Y representsC₁₋₆alkyl-NH—CO—, the suitable substituted anilines of formula (III^(d))are generally prepared according to reaction scheme 7.

In a first step the known 2-nitro-benzoic acids (XX) are amidated to theintermediates of formula (XXII) under art known conditions, for example,using a hydroxylated amine of formula (XXI) that is added dropwise to amixture of (XX) in CH₂Cl₂ in the presence of1,1′carbonylbis-1H-imidazole.

Next the primary free alcohol is protected using art known procedures,for example, using an esterification reaction with acetic anhydride inthe presence of pyridine.

The thus obtained intermediate of formula (XXIII) is subsequentlyreduced according to standard conditions, for example, usinghydrogenolysis (H₂, Pt/C, thiophene, MeOH) or tin(II)chloride(SnCl₂.H₂O, EtOH) to yield the substituted anilines of formula(III^(d)).

For those compounds where X² represents a direct bond the suitablesubstituted anilines of formula (III^(e)) are generally preparedaccording to reaction scheme 8. In a first step the known2-nitro-benzaldehydes (XIII) are alkenated to the intermediates offormula (XXV) under art known conditions, for example, using the WittigReaction with the appropriate phosphonium salt of formula (XXIV).

Following esterification of the free carboxylic acid under standardconditions for example, using ethanol under acidic conditions, theintermediate of formula (XXVI) are reduced to yield the desiredsubstituted anilines of formula (III^(e)).

Those compounds of formula (I′^(b)) wherein —X₁—Y—X₂ comprises anamine-amide linker, i.e. —X₁—Y—X₂— represents—O—C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-NR¹²—C₁₋₂alkyl-,—O—C₁₋₃alkyl-NH—CO-Het²⁰-C₁₋₂alkyl- or—C₁₋₆alkyl-NH—CO—CH₂-Het²²-O—C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—C₁₋₂alkyl- wereeither prepared according to reaction scheme 9 in case m is 1, 2 or 4,or by reaction scheme 10 in case m is 3.

To a solution of N-benzyl amino acid 4 or 9 (See Scheme 5a and 5b) inisopropanol is added one equivalent of chloroquinazoline 10 (Scheme 9a).The resulting solution is stirred for 2-24 h at 80° C. to give 11 (LCMSmonitoring). Next, the mixture is cooled to RT and a 6 N methanolicsolution of ammonia is added. After stirring for one hour, the solutionis evaporated to dryness. The crude phenol 12 is then redissolved in dryDMF and, upon addition of 5 equivalents of cesium carbonate, stirred forone h at RT. To the resulting phenolate is then added 1-1.2 eq (toprevent overalkylation) of Boc-aminoalkyl bromide, and the mixture isstirred overnight at RT, evaporated to dryness, redissolved indichloromethane and filtered over dicalite to remove cesium salts. Thisyields the crude Boc-aminoalkylated phenols 13.

As shown in scheme 9b, the ester function is then hydrolyzed, and Bocgroup(s) removed, by stirring a dioxane solution of 13 overnight at 60°C. in the presence of 6 N HCl (R=Me, Et) or at RT in the presence ofTFA/CH₂Cl₂MS (90:8:2) (R=tBu). After evaporation to dryness, theresulting amino acid 14 is redissolved in dry DMF and, upon addition of6 eq of DIPEA, added dropwise to a solution of 3 eq HBTU (or PyBOP)² indry DMF. Stirring this solution for 1 h at RT, followed by evaporationof the solvent yields the crude macrocycle 15a, which is purified by RPHPLC. A pre-purification can be done by dissolving the residue in CH₂Cl₂and washing it with saturated sodium bicarbonate in water, followed bydrying on potassium carbonate and removal of the solvent. The yield forthis sequence is 10-65% starting from the aniline 4 or 9.2 PyBop generates tris(pyrrolidino)phosphinoxide, which is oftendifficult to separate from the macrocycle. HBTU generatestetramethylurea, which is more easy to remove.

A Cbz group, if present, can be removed prior purification by dissolvingthe crude macrocycle 15a (R″″=Cbz) in 48% aqueous HBr and stirring for1-2 h at room temperature (RT). After concentration of the reactionmixture and quenching with solid potassium carbonate, the deprotectedmacrocycle 15b is obtained by extraction with CH₂Cl₂ (with addedmethanol in case of solubility problems), and is similarly purified byRP HPLC. The yield for Cbz deprotection is quantitative by LCMS.

To a solution of N-benzyl amino acid 4 or 9 in isopropanol is added oneequivalent of chloroquinazoline 10 (scheme 10a). The resulting solutionis stirred for 2-24 h at 80° C. to give 11. Next, the mixture is cooledto RT and a 6 N methanolic solution of ammonia is added. After stirringfor one hour, the solution is evaporated to dryness. The crude phenol 12is then redissolved in dry DMF and, upon addition of 5 equivalents ofcesium carbonate, stirred for one hour at RT. To the resulting phenolateis then added 0.8 eq (to prevent overalkylation) of4-bromobutyronitrile, and the mixture is stirred overnight at RT,evaporated to dryness, redissolved in dichloromethane and filtered overdicalite to remove cesium salts.

Crude 16 is then thoroughly dried, redissolved in 6 N ammonia/MeOH (toprevent dimerisation) and, after addition of some thiophene solution inDIPE (to prevent dechlorination), treated with wet Raney nickel under 1atm hydrogen pressure at 14° C. (scheme 10b). After consumption of 2equivalents of hydrogen gas (typically after 16-24 h), the mixture isfiltered over dicalite and concentrated to provide the crude amine 17.The ester function is then hydrolyzed to 18 (and, if R′″=Boc, the Bocgroup removed) by stirring a dioxane solution of 17 overnight in thepresence of 6 N HCl (R=Me, Et). After evaporation to dryness, theresulting amino acid 18 is redissolved in dry DMF and, upon addition of6 eq of DIPEA, added dropwise to a solution of 3 eq HBTU (or PyBOP) indry DMF. Stirring this solution for 1 h at RT, followed by evaporationof the solvent yields the crude macrocycle 19, which is purified by RPHPLC. A pre-purification can be done by dissolving the residue in CH₂Cl₂and washing it with saturated sodium bicarbonate in water. The yield forthis sequence is 4-30% starting from the aniline 4 or 9.

Those compounds of formula (I′^(b)) wherein —X₁—Y—X₂— comprises anamine-amine linker, i.e. —X₁—Y—X₂— represents—O—C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-NR¹²—C₁₋₂alkyl- were generally preparedaccording to reaction scheme 11.

To a solution of5-chloro-2-{[2,2-dimethoxyethyl)(methyl)amino]methyl}aniline 20 or thecorresponding dioxolane (prepared via reductive amination Scheme 5b) inisopropanol is added one equivalent of chloroquinazoline 10. Theresulting solution is stirred for 7-8 h at 80° C. to give 21. Next, themixture is cooled to RT and a 6 N methanolic solution of ammonia isadded to remove the acetyl group. After stirring for one hour, thesolution is evaporated to dryness. To the crude phenol 22 is then added5 eq of cesium carbonate and, after stirring for 1 h, Boc-aminoalkylbromide (1.0-1.2 eq) or 5-bromobutyronitrile (0.8 eq), and the mixtureis subsequently stirred overnight at RT evaporated to dryness,redissolved in dichloromethane and filtered over dicalite to removecesium salts. This yields the protected aminoalkyl-substituted phenols23. The butyronitrile-substituted phenol is first hydrogenated to thecorresponding amine under the abovementioned conditions.

Next the compounds are dissolved in 6 N HCl and dioxane, and theresulting mixture is stirred for about 24 h at 60° C. (LCMS monitoring,formation of imine 24 is observed) (scheme 11). After completion of thereaction, the mixture is poured carefully into an ice-cooled sodiumbicarbonate solution or evaporated to dryness (slow, leads todecomposition). In the first case, the imine is extracted with methylenechloride and, after drying on potassium carbonate, immediately reducedto the corresponding amine by addition of sodium-triacetoxyborohydride.In the latter case, the oily residue is redissolved in methylenechloride and excess sodium triacetoxyborohydride is added to yield thecorresponding amine. The crude macrocycle 25 is obtained after additionof saturated sodium carbonate, extraction with dichloromethane followedby drying on potassium carbonate and removal of the solvent, and can bepurified RP HPLC.

Those compounds of formula (I′^(b)) wherein —X₁—Y—X₂— comprises anamide-amide linker, i.e. —X₁—Y—X₂— represents—O—C₁₋₄alkyl-CO—NH—CR¹⁵R¹⁹—CO—R¹²—C₁₋₂alkyl-,—O—C₁₋₄alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—NR¹²—C₁₋₂alkyl-, orO—C₁₋₄alkyl-CO-Het²⁰-CO—NR¹²—C₁₋₂alkyl- were generally preparedaccording to reaction scheme 12.

Reagents and conditions: a) i) PL-DCC Resin, HOBt, DCM/DMF, RT, 5 h; ii)Polystyrene-methylisocyanate, (polystyrylmethyl)trimethylammoniumbicarbonate, RT, 12 h; b) i) chloro quinazoline, iPrOH, 55° C., 3 h; ii)7N NH₃ in MeOH, rt, 2 h; c) ClCH₂(CH₂)_(m)CO₂CH₃, K₂CO₃; d) conc. HCl,H₂O, dioxane, 60° C., 12 h; e) PyBOP, DIPEA, DMF, RT, 3 h.

In this procedure the aniline 26 is coupled with the appropriate aminoprotected amino acid, to form the amide of formula 27 using art knownconditions, see for example A42 d) hereinbelow. Subsequent coupling withthe chloroquinazoline under standard conditions, for example stirred inpropanol at an elevated temperature ranging form 40-100° C. during 3-12h, provides the intermediates of formula 28. Alkylation with theappropriate haloacetate followed by deprotection and ring closure, i.e.amide formation using art known conditions, provides the compounds offormula 30. Deprotection of the intermediates of formula 28 can be doneas described in Protective Groups in Organic Synthesis by T. W. Greeneand P. G. M. Wuts, 3^(rd) edition, 1998.

Alternatively, the compounds of formula (I) are prepared by ring closingmetathesis of the corresponding olefins (Scheme 13). This reaction isparticular useful for those compounds of formula (I) wherein Yrepresents —C₃₋₉alkenyl-, —C₃₋₉alkyl-, —C₃₋₇alkyl-CO—NH— optionallysubstituted with amino, mono- or di(C₁₋₄alkyl)amino orC₁₋₄alkyloxycarbonylamino-, or Y represents —C₃₋₇alkenyl-CO—NH—optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino orC₁₋₄alkyloxycarbonylamino-hereinafter referred to as the compounds offormula (I′^(c)).

In a first step the aniline of formula (III^(c)) is coupled to the4-chloroquinazoline (II^(b)) under standard conditions, for examplestirred in propanol art an elevated temperature ranging from 40-100° C.during 3-12 h. Deprotection of the intermediate of formula (IV^(c)) asdescribed in Protective Groups in Organic Synthesis by T. W. Greene andP. G. M. Wuts, 3^(rd) edition, 1998, followed by alkylation with theappropriate alkyl bromides (XXXII) under art known conditions, such asfor example stirring overnight at room temperature in the presence of—Cs₂CO₃ in a reaction inert solvent such as for exampleN,N-dimethylformamide (DMF), provides the olefins of formula (XXXIII).Ring closing metathesis as described in Advanced Organic Chemistry by J.March, 3^(rd) edition, 1985, p1036-1039 provides the compounds offormula (I′^(c)) that can optionally be reduced using art knownprocedures, for example, stirring for 3-10 h at room temperature underH₂-atmosphere in the presence of Pt/C in tetrahydrofuran (THF)/methanolas solvent. The aniline of formula (III^(e)) is synthesized similar tothe synthesis of the amide of formula 27 (Scheme 12 above) by acylationof the corresponding amine.

Where necessary or desired, any one or more of the following furthersteps in any order may be performed:

-   (i) removing any remaining protecting group(s);-   (ii)(converting a compound of formula (I) or a protected form    thereof into a further compound of formula (I) or a protected form    thereof;-   (iii) converting a compound of formula (I) or a protected form    thereof into a N-oxide, a salt, a quaternary amine or a solvate of a    compound of formula (I) or a protected form thereof;-   (iv) converting a N-oxide, a salt, a quaternary amine or a solvate    of a compound of formula (I) or a protected form thereof into a    compound of formula (I) or as protected form thereof;-   (v) converting a N-oxide, a salt, a quaternary amine or a solvate of    a compound of formula (I) or a protected form thereof into another    N-oxide, a pharmaceutically acceptable addition salt a quaternary    amine or a solvate of a compound of formula (I) or a protected form    thereof;-   (vi) where the compound of formula (I) is obtained as a mixture    of (R) and (S) enantiomers resolving the mixture to obtain the    desired enantiomer.

Compounds of formula (I), N-oxides, addition salts, quaternary aminesand stereochemical isomeric forms thereof can be converted into furthercompounds according to the invention using procedures known in the art.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups.

Functional groups, which it is desirable to protect, include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₍₁₋₆₎alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

Additionally, the N-atoms in compounds of formula (I) can be methylatedby art-known methods using CH₃—I in a suitable solvent such as, forexample 2-propanone, tetrahydrofuran or dimethylformamide.

The compounds of formula a) can also be converted into each otherfollowing art-known procedures of functional group transformation ofwhich some examples are mentioned hereinafter.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or, earl alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g. counter-current distribution,liquid chromatography and the like.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diasteromeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials as used in the reactionprocedures mentioned hereinabove are known compounds and may becommercially available or may be prepared according to art-knownprocedures. However, in the synthesis of the compounds of formula (I),the present invention further provides;

-   a) the intermediates of formula (III)-   the pharmaceutically acceptable addition salts and the    stereochemically isomeric forms thereof, wherein-   V represents hydrogen or a protective group preferably selected from    the group consisting of methylcarbonyl, t-butyl, methyl, ethyl,    benzyl or trialkylsilyl;-   Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₃₋₇alkyl-CO—NH—    optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or    C₁₋₄alkyloxycarbonylamino-, —C₃₋₇alkenyl-CO—NH— optionally    substituted with amino, mono- or di(C₁₋₄alkyl)amino or    C₁₋₄alkyloxycarbonylamino-,    -   —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-,    -   —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,    -   —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—,        —C₁₋₆alkyl-NH—CO—,    -   —C₁₋₃alkyl-NH—CS—Het²⁰-C₁₋₃alkyl-NH—CO-Het²⁰-,        C₁₋₂alkyl-CO-Het²¹-CO—, -Het²²-CH₂—CO—NH—C₁₋₃alkyl-,        —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-,        —C₁₋₇alkyl-CO—, —C₁₋₆alkyl-CO—C₁₋₆alkyl-,    -   —CO-Het²⁰, —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—,        —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—, —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—,        —C₁₋₂alkyl-NR²¹—CH₂—CO—NH—C₁₋₃alkyl-, or —NR²²—CO—C₁₋₃alkyl-NH—;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹², —NR¹²—C₁₋₂alkyl-, CH₂—, —O—N═CH— or —C₁₋₂alkyl-;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-, halo-phenyl-carbonylamino-,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-,    aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl,    C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-,    C₁₋₆alkoxy-, Ar⁵, Ar⁴-oxy-, dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-,    Het¹⁸-C₁₋₄alkyl-, phenyl-C₁₋₄alkyl-oxy-carbonyl-, Het⁷,    C₂₋₄alkenylcarbonyl- optionally substituted with    Het⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or R¹² represents phenyl optionally    substituted with one or where possible two or more substituents    selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-;-   R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or    phenyl optionally substituted with one or where possible two or more    substituents selected from hydrogen, hydroxy, amino or    C₁₋₄alkyloxy-;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen,    C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-;-   R¹⁶ and R¹⁷ each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with phenyl, indolyl, methylsulfide, hydroxy,    thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine,    imidazoyl or guanidino;-   R¹⁸ and R¹⁹ each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with phenyl, indolyl, methylsulfide, hydroxy,    thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, mine,    imidazoyl or guanidino;-   R²⁰ and R²² each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with hydroxy or C₁₋₄alkyloxy;-   R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or    -   R²¹ represents mono- or -di(C₁₋₄alkyl)amino-C₁₋₄ alkyl-carbonyl-        optionally substituted with hydroxy, pyrimidinyl, dimethylamine        or C₁₋₄alkyloxy;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, oxazolyl,    imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl    wherein said Het¹ is optionally substituted with amino, C₁₋₄alkyl,    hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het¹³ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁴ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋allkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁵ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxy    alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl; and-   Het¹⁷ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆ cycloalkyl,    -   hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or        polyhydroxy-C₁₋₄alkyl-;-   Het²⁰, Het²¹ and Het²² each independently represent a heterocycle    selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or    -piperidinyl optionally substituted with one or where possible two    or more substituents selected from hydroxy,    -   C₁₋₄alkyl, hydroxy-C₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-;-   Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl    optionally substituted with cyano, C₁₋₄alkylsulfonyl-,    C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl,    aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.

In one embodiment the intermediates of formula (III) consists of theintermediates of formula (III) wherein one or more of the followingrestrictions apply;

-   V represents hydrogen or a protective group preferably selected from    the group consisting of methylcarbonyl, t-butyl, methyl, ethyl,    benzyl or trialkylsilyl;-   Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    -   —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,    -   —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—,        —C₁₋₆alkyl-NH—CO—,    -   —C₁₋₇alkyl-CO—, C₁₋₆alkyl-CO—C₁₋₆alkyl;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹²,    -   —NR²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or C₁₋₂alkyl;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo; and-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het⁶-carbonyl-,    -   C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono-        or di(C₁₋₄alkyl)aminocarbonyl-, -Het¹ formyl, C₁₋₄alkyl-,        C₂₋₆alkynyl-,    -   C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-,        dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-,    -   phenyl-C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷, Het⁸-C₁₋₄alkyl-,    -   —C₂₋₄alkenylcarbonyl- optionally substituted with        Het⁹-C₁₋₄alkylaminocarbonyl-,    -   C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl        optionally substituted with one or where possible two or more        substituents selected from hydrogen, hydroxy, amino or        C₁₋₄alkyloxy-;-   R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het⁴-C₁₋₄alkyl- or phenyl    optionally substituted with one or where possible two or more    substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyl-;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen:    C₁₋₄-alkyl,    -   Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het¹³ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄allkyl, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁴ represent a heterocycle-selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-,    C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁵ represent a heterocycle selected from morpholinyl;    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁶ represents a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl; and-   Het¹⁷ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl    optionally substituted with cyano, C₁₋₄alkylsulfonyl-,    C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl,    aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.

In particular the intermediates of formula (III) wherein one or more ofthe following restrictions apply;

-   i) V represents hydrogen, methyl or ethyl;-   ii) Y represents —C₃₋₉alkyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO—;-   iii) Y represents —C₁₋₅alkyl-oxy-C₁₋₅alkyl, C₁₋₂alkyl-CO-Het²¹-CO—,    —CO—C₁₋₇alkyl-, or —CO-Het²⁰;-   iv) X² represents a direct bond, O, —O—C₁₋₂alkyl-, NR¹²,    —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or C₁₋₂alkyl;-   v) X² represents —NR¹²—C₁₋₂alkyl- or C₁₋₂alkyl;-   vi) R¹ represents hydrogen, cyano, halo or hydroxy, preferably halo;-   vii) R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-,    Ar⁵ or Het¹; preferably halo;-   viii) R² represents hydrogen, cyano, halo, hydroxy, C₂₋₆alkynyl- or    Het¹; in particular R² represents hydrogen, cyano, halo, hydroxy, or    Ar⁵;-   ix) R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyloxycarbonyl or    phenyl-C₁₋₄alkyl-oxy-carbonyl-;-   x) R¹³ represents Het¹⁴-C₁₋₄alkyl, in particular    morpholinyl-C₁₋₄alkyl;-   xi) Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   xii) Het¹⁶ represents a heterocycle selected from piperidinyl or    pyrrolidinyl;-   xiii) Het²⁰ represents piperidine, piperazine, pyrrolidinyl or    2-pyrrolidinonyl wherein said Het²⁰ is optionally substituted with    hydroxy.    b) the intermediates of formula (XXX)    the pharmaceutically acceptable addition salts and the    stereochemically isomeric forms thereof, wherein-   Y1 and Y2 each independently represent a C₁₋₅alkyl, C₁₋₆alkyl,    CO—C₁₋₆alkyl, CO—C₁₋₅alkyl, Het²²-CH₂—CO, CO—CR¹⁶R¹⁷NH—, Het²⁰,    CR¹⁸R¹⁹—CO—, CH₂—CO—NH—C₁₋₃alkyl-, —C₁₋₂alkyl-NR²¹-CH₂—CO— or    CO—C₁₋₃alkyl-NH—;-   X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹¹, —NR¹¹—C₁₋₂alkyl-, —CH₂—O—N═C— or —C₁₋₂alkyl-;-   X² represents a direct bond, O —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆-alkyl-, halo-phenyl-carbonylamino-,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-,    aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl,    C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-,    C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R³ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one    or more substituents selected from halo, C₁₋₄alkyloxy-, amino-,    mono- or di(C₁₋₄alkyl)amino-,    -   C₁₋₄alkyl-sulfonyl- or phenyl;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl,    Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl,    Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-,    Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-;-   R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₄alkyl,    C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or    polyhydroxy-C₁₋₄alkyl-;-   R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-,    C₂₋₄alkenylcarbonyl-optionally substituted with    Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl-, or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷,    Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with    Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹⁶ and R¹⁷ each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with phenyl, indolyl, methylsulfide, hydroxy,    thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine,    imidazoyl or guanidino;-   R¹⁸ and R¹⁹ each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with phenyl, indolyl, methylsulfide, hydroxy,    thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine,    imidazoyl or guanidino,-   R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or R²¹    represents mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-carbonyl-    optionally substituted with hydroxy, pyrimidinyl, dimethylamine or    C₁₋₄alkyloxy;-   R²³ represents Ar³, Ar⁴—C₁₋₄ alkyl, C₁₋₄-alkyl, C₂₋₆alkenyl    optionally substituted with Het¹² or R¹⁷ represents C₁₋₄alkyl    substituted with one or where possible two or more substituents    selected from C₁₋₄alkyloxy, hydroxy, halo, Het², NR⁷R⁸,    NR⁹R¹⁰-carbonyl or Het³-carbonyl;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-,    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or    di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-;-   Het³, Het⁴ and Het⁸ each independently represent a heterocycle    selected from morpholinyl, piperazinyl, piperidinyl, furanyl,    pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or    Het⁸ is optionally substituted with one or where possible two or    more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-,    C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or    di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-;-   Het⁵ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het⁶ and Het⁷ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het⁹ and Het¹⁰ each independently represent a heterocycle selected    from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl,    dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is    optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or    amino-C₁₋₄alkyl-;-   Het¹¹ represents a heterocycle selected from indolyl or-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het¹² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-;-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl; and-   Het¹⁷ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het²⁰, Het²¹ and Het²² each independently represent a heterocycle    selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or    piperidinyl optionally substituted, with one or where possible two    or more substituents selected from hydroxy, —C₁₋₄alkyl,    hydroxy-C₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-;-   Het²³ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Ar¹, Ar³, Ar⁴ and Ar⁵ each independently represent phenyl optionally    substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-,    aminosulfonylamino-, hydroxy-C₁₋₄alkyl, aminosulfonyl-, hydroxy-,    C₁₋₄alkyloxy- or C₁₋₄alkyl.

In one embodiment the intermediates of formula (XXX) consists of theintermediates of formula (XXX) wherein one or more of the followingrestrictions apply;

-   Y₁ and Y₂ each independently represent C₁₋₅alkyl, CO—C₁₋₅alkyl or    CO—CHR¹⁶—NH—;-   X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹¹, —NR¹¹—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, CO—C₁₋₂alkyl-,    NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or C₁₋₂alkyl;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo; and-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-,    aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl,    C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-,    -   C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R³ represents hydrogen;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R⁷ and R⁵ are each independently selected from hydrogen, C₁₋₄alkyl,    Het⁸, aminosulfonyl-, mono or -di(C₁₋₄alkyl)-aminosulfonyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl,    Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-,    Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-;-   R⁹ and R¹⁰ are each, independently selected from hydrogen,    C₁₋₄alkyl, C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-;-   R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-,    C₂₋₄alkenylcarbonyl-optionally substituted with    Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het⁷,    Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with    Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄-alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or —C₁₋₄alkyloxy-;-   R¹⁶ represents hydrogen or C₁₋₄alkyl optionally substituted with    phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl,    aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;-   R²³ represents Ar³, Ar⁴—C₁₋₄alkyl, C₁₋₄alkyl, C₂₋₆alkenyl optionally    substituted with Het¹² or R¹⁷ represents C₁₋₄alkyl substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyloxy, hydroxy, halo, Het², NR⁷R⁸, NR⁹R¹⁰-carbonyl or    Het³-carbonyl-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-,    mono- or di(C₁₋₄alkyl)amino-4C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or    di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-;-   Het³, Het⁴ and Het⁸ each independently represent a heterocycle    selected from morpholinyl, piperazinyl, -piperidinyl, furanyl,    pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or    Het⁸ is optionally substituted with one or where possible two or    more substituents selected from hydroxy-, amino, C₁₋₄alkyl-;    -   C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or        di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-;-   Het⁵ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het⁶ and Het⁷ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het⁹ and Het¹⁰ each independently represent a heterocycle selected    from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl,    dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is    optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or    amino-C₁₋₄alkyl-;-   Het¹¹ represents a heterocycle selected from indolyl or-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het¹² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-;-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl; and-   Het¹⁷ represent a heterocycle selected from pyrrolidinyl or    piperidinyl optionally substituted with one or where possible two or    more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally, substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Ar¹, Ar³, Ar⁴ and Ar⁵ each independently represent phenyl optionally    substituted with -cyano, C₁₋₄alkylsulfonyl-,    C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl,    aminosulfonyl-, hydroxy-, —C₁₋₄alkyloxy- or C₁₋₄alkyl.

In particular the intermediates of formula (XXX) wherein one or more ofthe following restrictions apply;

-   i) X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or    —NR¹¹—C₁₋₂alkyl-; in a particular embodiment X¹ represents —NR¹¹—,    —O— or O—CH₂—;-   ii) X² represents a direct bond, O, O—C₁₋₂alkyl-, —O—N═CH—, NR¹² or    NR¹²—C₁₋₂alkyl-; in a particular embodiment X² represents a direct    bond, —C₁₋₂alkyl-, —O—C₁₋₂alkyl, —O— or O—CH₂—;-   iii) R¹ represents hydrogen, cyano, halo or hydroxy, preferably    halo;-   iv) R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-,    Ar⁵ or Het¹; In a further embodiment R² represents hydrogen, cyano,    halo, hydroxy, C₂₋₆alkyl- or Het¹; in particular R² represents    hydrogen, cyano, halo, hydroxy, or Ar⁵;-   v) R²³ represents hydrogen, C₁₋₄alkyl or R¹⁷ represents C₁₋₄alkyl    substituted with one or where possible two or more substituents    selected from C₁₋₄alkyloxy- or Het²-;-   vi) R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   vii) Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   viii) Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-; In a    further embodiment Het² represents a heterocycle selected from    morpholinyl or piperidinyl optionally substituted with C₁₋₄alkyl-,    preferably methyl;-   ix) Het³ represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het³ is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   x) Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   xi) Het¹⁶ represents a heterocycle selected from piperidinyl or    pyrrolidinyl.

c) the intermediates of formula (XXXIII)

the pharmaceutically acceptable addition salts and the stereochemicallyisomeric forms thereof, wherein

-   m represents 1, 2, 3 or 4;-   X² represents a direct bond O, —O—C₁₋₂alkyl, CO, —CO—C₁₋₂alkyl-,    NR¹², —NR¹²—C₁₋₂alkyl-, —CH₁₂, —O—N═CH— or C₁₋₂alkyl;-   Y₃ represents a C₁₋₅alkyl, CO—C₁₋₅alkyl or CO—CR¹⁶R¹⁷—NH— or    C₁₋₅alkyl-CO— optionally substituted with amino, mono- or    di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-, halo-phenyl-carbonylamino-,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-,    aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl,    C₁₋₄alkyl-, C₂₋₆alkynyl-,    -   C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-,        dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R³ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one    or more substituents selected from halo, C₁₋₄alkyloxy-, amino-,    mono- or di(C₁₋₄alkyl)amino-,    -   C₁₋₄alkyl-sulfonyl- or phenyl;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-,    Het¹⁸-C₁₋₄alkyl-, phenyl-C₁₋₄alkyl-oxy-carbonyl-Het¹⁷,    C₂₋₄alkenylcarbonyl- optionally substituted with    Het⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹⁶ and R¹⁷ each independently represents hydrogen or C₁₋₄alkyl    optionally substituted with phenyl, indolyl, methylsulfide, hydroxy,    thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine,    imidazoyl or guanidino;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl mono or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    -   hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or        polyhydroxy-C₁₋₄alkyl-; and-   Ar¹ and Ar⁵ each independently represent phenyl optionally    substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-,    aminosulfonylamino-, hydroxy-C₁₋₄alkyl, aminosulfonyl-, hydroxy-,    C₁₋₄alkyloxy- or C₁₋₄alkyl.

In particular the intermediates of formula (XXXIII) wherein one or moreof the following restrictions apply;

-   i) X² represents a direct bond, C₁₋₂alkyl, NR¹² or —NR¹²—C₁₋₂alkyl-;    in a particular embodiment X² represents —NR¹²—C₁₋₂alkyl- or    C₁₋₂alkyl;-   ii) Y₃ represents a C₁₋₅alkyl, CO—CR¹⁶R¹⁷—NH—, or —C₁₋₅alkyl-CO—; in    a particular embodiment Y₃ represents —C₁₋₅alkyl-CO—;-   iii) R¹ represents hydrogen, cyano, halo or hydroxy, preferably    halo;-   iv) R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, —C₂₋₆alkynyl-,    Ar⁵ or Het¹; In a further embodiment R² represents hydrogen, cyano,    halo or hydroxy; in particular R² represents hydrogen, cyano, halo,    hydroxy, or Ar⁵;-   v) R³ represents hydrogen;-   vi) R¹² represents hydrogen or C₁₋₄alkyl;-   vii) R¹⁶ represents hydrogen or C₁₋₄alkyl substituted with hydroxy;-   viii) R¹⁷ represents hydrogen or C₁₋₄alkyl, in particular hydrogen    or methyl;-   ix) Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   x) Het¹⁶ represents a heterocycle selected from piperidinyl or    pyrrolidinyl;-   xi) Ar⁵ represents phenyl.

It is also an object of the present invention to provide the use of theintermediates of formula (III), (XXX) or (XXXIII) in the synthesis of acompound of formula (I).

The compounds of the present invention, including the compounds offormula (I) and the intermediates of formula (III), (XXX) and (XXXIII)are useful because they possess pharmacological properties. They cantherefore be used as medicines.

As described in the experimental part hereinafter, the growth inhibitoryeffect and anti-tumour activity of the present compounds has beendemonstrated in vitro, in enzymatic assays on the receptor tyrosinekinases EGFR, ErbB2, ErbB4, FlT3, BLK or the Sar kinase family such asfor example Lyn, Yes cSRC. In an alternative assay, the growthinhibitory effect of the compounds was tested on a number of carcinamocell lines, in particular in the ovarian carcinoma cell line SKOV3 andthe squamous carcinoma cell line A431 using art known cytotoxicityassays such as MTT.

Accordingly, the present invention provides the compounds of formula (I)and their pharmaceutically acceptable N-oxides, addition salts,quaternary amines and stereochemically isomeric forms for use intherapy. More particular in the treatment or prevention of cellproliferation mediated diseases. The compounds of formula (I) and theirpharmaceutically acceptable N-oxides, addition salts, quaternary aminesand the stereochemically isomeric forms may hereinafter be referred toas compounds according to the invention.

Disorders for which the compounds according to the invention areparticularly useful are atherosclerosis, restenosis, cancer and diabeticcomplications e.g. retinopathy.

In view of the utility of the compounds according to the invention,there is provided method of treating a cell proliferative disorder suchas atherosclerosis, restenosis and cancer, the method comprisingadministering to an animal in need of such treatment, for example, amammal including humans, suffering from a cell proliferative disorder, atherapeutically effective amount of a compound according to the presentinvention.

Said method comprising the systemic or topical administration of aneffective amount of a compound according to the invention, to animals,including humans. One skilled in the art will recognize that atherapeutically effective amount of the EGFR inhibitors of the presentinvention is the amount sufficient to induce the growth inhibitoryeffect and that this amount varies inter alia, depending on the size,the type of the neoplasia, the concentration of the compound in thetherapeutic formulation, and the condition of the patient. Generally, anamount of EGFR inhibitor to be administered as a therapeutic agent fortreating cell proliferative disorder such as atherosclerosis, restenosisand cancer, will be determined on a case by case by an attendingphysician.

Generally, a suitable dose is one that results in a concentration of theEGFR inhibitor at the treatment site in the range of 0.5 nM to 200 μM,and more usually 5 nM to 10 μM. To obtain these treatmentconcentrations, a patient in need of treatment likely will beadministered between 0.01 mg/kg to 300 mg/kg body weight, in particularfrom 10 mg/kg to 100 mg/kg body weight. As noted above, the aboveamounts may vary on a case-by-case basis. In these methods of treatmentthe compounds according to the invention are preferably formulated priorto admission. As described herein below, suitable pharmaceuticalformulations are prepared by known procedures using well known andreadily available ingredients.

Due to their high degree of selectivity as EGFR inhibitors, thecompounds of formula (I) as defined above, are also useful to mark oridentify the kinase domain within the receptor tyrosine kinasereceptors. To this purpose, the compounds of the present invention canbe labelled, in particular by replacing, partially or completely, one ormore atoms in the molecule by their radioactive isotopes. Examples ofinteresting labelled compounds are those compounds having at least onehalo which is a radioactive isotope of iodine, bromine or fluorine; orthose compounds having at least one ¹¹C-atom or tritium atom.

One particular group consists of those compounds of formula (I) whereinR¹ is a radioactive halogen atom. In principle, any compound of formula(I) containing a halogen atom is prone for radiolabelling by replacingthe halogen atom by a suitable isotope. Suitable halogen radioisotopesto this purpose are radioactive iodides, e.g. ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I;radioactive bromides, e.g. ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br, and radioactivefluorides, e.g. ¹⁸F. The introduction of a radioactive halogen atom canbe performed by a suitable exchange reaction or by using any one of theprocedures as described hereinabove to prepare halogen derivatives offormula (I).

Another interesting form of radiolabelling is by substituting a carbonatom by a ¹¹C-atom or the substitution of a hydrogen atom by a tritiumatom.

Hence, said radiolabelled compounds of formula (I) can be used in aprocess of specifically marking receptor sites in biological material.Said process comprises the steps of (a) radiolabelling a compound offormula (I), (b) administering this radio-labelled compound tobiological material and subsequently (c) detecting the emissions fromthe radiolabelled compound.

The term biological material is meant to comprise every kind of materialwhich has a biological origin. More in particular this term refers totissue samples, plasma or body fluids but also to animals, speciallywarm-blooded animals, or parts of animals such as organs.

When used in in vivo assays, the radiolabelled compounds areadministered in an appropriate composition to an animal and the locationof said radiolabelled compounds is detected using imaging techniques,such as, for instance, Single Photon Emission Computerized Tomography(SPECT) or positron Emission Tomography (PET) and the like. In thismanner the distribution of the particular receptor sites throughout thebody can be detected and organs containing said receptor sites can bevisualized by the imaging techniques mentioned hereinabove. This processof imaging an organ by administering a radiolabelled compound of formula(I) and detecting the emissions from the radioactive compound alsoconstitutes a part of the present invention.

In yet a further aspect, the present invention provides the use of thecompounds according to the invention in the manufacture of a medicamentfor treating any of the aforementioned cell proliferative disorders orindications.

The amount of a compound according to the present invention, alsoreferred to here as the active ingredient, which is required to achievea therapeutical effect will be, of course, vary with the particularcompound, the route of administration, the age and condition of therecipient, and the particular disorder or disease being treated. Asuitable daily dose would be from 0.01 kg to 300 mg/kg body weight, inparticular from 10 mg/kg to 100 mg kg/body weight. A method of treatmentmay also include administering the active ingredient on a regimen ofbetween one and four intakes per day.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition.Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a compound according to the present invention,together with a pharmaceutically acceptable carrier or diluent. Thecarrier or diluent must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipients thereof.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18^(th) ed., Mack Publishing Company 1990, see especially Part8: Pharmaceutical preparations and their Manufacture). A therapeuticallyeffective amount of the particular compound, in base form or additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for systemic administrationsuch as oral, percutaneous or parenteral administration; or topicaladministration such as via inhalation, a nose spray, eye drops or via acream, gel, shampoo or the like. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions: or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wettable agent, optionally combined withsuitable additives of any nature in minor proportions, which additivesdo not cause any significant deleterious effects or the skin. Saidadditives may facilitate the administration to the skin and/or may behelpful for preparing the desired compositions. These compositions maybe administered in various ways, e.g., as a transdermal patch, as aspot-on or as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Experimental Part

Hereinafter, the term ‘RT’ means room temperature, ‘ADDP’ means1,1′-(azodicarbonyl)dipiperidine, ‘DCM’ dichloromethane, ‘DMA’ meansdimethylacetamide, ‘DME’ means dimethyl ether, ‘DMF’ meansN,N-dimethylformamide, ‘DMSO’ means dimethylsulfoxide, ‘DIPE’ meansdiisopropyl ether, ‘DIPEA’ meansN-ethyl-N-(1-methylethyl)-2-propanamine, ‘EtOH’ means ethanol, ‘EtOAc’means ethyl acetate, ‘HBTU’ means1-[bis(dimethylamino)methylene]-H-benzotriazoalium,hexafluorophosphate(1-), 3-oxide) ‘LAH’ means lithiumaluminiumhydridei.e. LiAlH₄, ‘TFA’ means trifluoroacetic acid and ‘THF’ meanstetrahydrofuran, ‘PyBOP’ means(1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-, (T-4)-phosphorus(1+), hexafluorophosphate(1-), ‘NaBH(OAc)₃’ means sodiumtriacetoxyborohydride, RP means reversed-phase.

A. Preparation of the Intermediates

EXAMPLE A1 a) Preparation of hexanoic acid,6-(2-methyl-6-nitrophenoxy)-, methyl ester (intermediate 1)

A mixture of 2-methyl-6-nitro-phenol (0.0065 mol) and K₂CO₃(0.026 mol)in N,N-dimethyl-formamide (DMF) (80 ml) was stirred at 50° C. for 15min., then 6-bromo-methyl ester hexanoic acid (0.0195 mol) was addeddropwise and the reaction mixture was stirred for 18 hours at 50° C.After completion, the reaction was quenched with ice-water and themixture was extracted 3 times with toluene. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated. The residue wasused as such in the next step, yielding 100% of intermediate 1.

b) Preparation of hexanoic acid, 6-(2-amino-6-methylphenoxy)-, methylester (intermediate 2)

A mixture of intermediate (0.013 mol) and ethylamine (0.5 g) in THF (100ml) vas hydrogenated with Pt/C 5% (2 g) as a catalyst. After uptake ofH₂ (3 equiv.), the reaction mixture was filtered over a small plug ofDicalite and the filtrate was concentrated, yielding 1.4 g ofintermediate 2 which was used as such in the next step.

c) Preparation of hexanoic acid,6-[2-[[6-(acetyloxy)-4-methoxy-4-quinazolinyl]amino]-6-methylphenoxy],methyl ester (intermediate 3)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline 0.0045intermediate 2(0.6056 mol) in 2-propanol (40 ml) was stirred andrefluxed for 1 day. The reaction mixture was concentrated and theresidue, treated with DIPE and this mixture was stirred overnight. Thesolid was collected by filtration, washed and dried, yieldingintermediate 3.

d) Preparation of hexanoic acid,6-[2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]-6-methylphenoxy]-,methyl ester (intermediate 4)

A solution of intermediate 3 (0.0045 mol) and NH₄OH (1.5 ml) in CH₃OH(50 ml) was stirred for 18 hours at RT and the solvent was evaporated,yielding intermediate 4 (impure, used as such in the next reactionstep).

e) Preparation of hexanoic acid,6-[2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]-6-methylphenoxy](intermediate 5)

A mixture of intermediate 4 (0.00024 mol), LiOH (0.00047 mol), THF (3ml), CH₃OH (1 ml) and H₂O (1 ml) was stirred and heated at 70° C. for 30min. and then the reaction mixture was allowed to reach RT. The organicsolvent (THF/CH₃OH) was evaporated and the aqueous concentrate wasneutralised with HCl (1N) filtered and the solid retained was washed anddried (vac.) at 65° C.; yielding 0.040 g of intermediate 5.

EXAMPLE A2 a) Preparation of hexanoic acid,6-(2-chloro-6-nitrophenoxy)-, methyl ester (intermediate 6)

A solution of 2-chloro-6-nitro- phenol 0.046 mol) inN,N-dimethylformamide (150 ml) was heated to 50° C., then K₂CO₃ (0.069mol) was added and the reaction mixture was stirred for 15 min.6-Bromo-,methyl ester hexanoic acid (0.069 mol) was added and themixture was stirred overnight. The reaction mixture was filtered and thefiltrate was concentrated and the residue was used as such in the nextstep, yielding 13.88 g of intermediate 6.

b) Preparation of hexanoic acid, 6-(2-amino-6-chlorophenoxy)-, methylester (intermediate 7)

A mixture of intermediate 6 (0.046 mol) and ethanime (2 g) in THF (ml)was hydrogenated with Pt/C 5% (3 g) as a catalyst in the presence ofDIPE (2 ml). After uptake of H₂ (3 equiv.), the reaction mixture wasfiltered over small plug of Dicalite the filtrate was concentrated,yielding intermediate 7.

c) Preparation of hexanoic acid,6-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-6-chlorophenoxy]-,methyl ester (intermediate 8)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.022mol) and intermediate 7 (0.022 mol) in 2-propanol (170 ml) was stirredand heated at 80° C. for 2 hours, concentrated and the residue waschromatographed over silica gel (eluent: DCM/CH₃OH 97/3). The productfractions were collected and the solvent was evaporated, yielding 5.1 gintermediate 8 (used as such in the next reaction step).

d) Preparation of 6-quinazolinol,4-[[3-chloro-2-[(6-hydroxyhexyl)oxy]phenyl]amino]-7-methoxy-(intermediate 9)

A mixture of LAH (0.0246 mol) in THF (40 ml) was stirred at RT. Asolution of intermediate 8 (0.006 mol) in THF (60 ml) was addeddropwise. The reaction mixture was stirred for 1 day then, extra LAH(0.0123 mol) was added portionwise. The mixture was stirred further overthe weekend then, H₂O (2 ml) was added dropwise, followed by thedropwise addition of a 15% NaOH soln. (2 ml) and H₂O (6 ml). Thismixture was stirred for 15 min filtered and the filtrate wasconcentrated. The residue was stirred in boiling CH₃CN, filtered and thesolid retained was dried (vac.) at 60° C. The solids were re-dissolvedin CH₃OH/DCM (10/90) and this mixture was neutralised with HCl (1N). Theorganic layer was separated, dried (MgSO₄), filtered and concentrated,yielding 1 g of intermediate 9.

EXAMPLE A3, a) Preparation of hexanoic acid,6-(4-chloro-2′-nitrophenoxy)-, methyl ester (intermediate 10)

A mixture of 4-chloro-6-nitro-phenol (0.029 mol) and K₂CO₃ (0.035 mol)in DMA (80 ml) was stirred at 50° C. for 30 min., then 6-bromo-,methylester hexanoic acid (0.035 mol) was added dropwise and the reactionmixture was stirred for another 1-8 hours at 50° C. After completion,the mixture was filtered and the filtrate was neutralised with HCl (1N),then poured onto ice water and stirred for 30 min. The resultingprecipitate was collected by filtration; washed, dissolved in DCM, dried(MgSO₄), filtered and concentrated, yielding intermediate 10 (used assuch in the next reaction step).

b) Preparation of hexanoic acid, 6-(2-amino-4-chlorophenoxy)-, methylester (intermediate 11)

A mixture of intermediate 10 (0.026 mol) and ethylamine (1 g) in THF(100 ml) was hydrogenated with Pt/C 5% (5 g) as a catalyst in thepresence of DIPE (1 ml). After uptake of H₂ (3 equiv.), and the reactionmixture was filtered over a small plug of Dicalite, the filtrate wasconcentrated, yielding intermediate 11.

c) Preparation of hexanoic acid,6-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenoxy]-,methyl ester (intermediate 12)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.014mol) and intermediate 11(0.014 mol) in 2-propanol (120 ml) was heated at80° C. and stirred for 3 hours. The reaction mixture was filtered andthe filtrate was concentrated. The residue was purified by columnchromatography over silica gel (eluent: DCM/CH₃OH 96.5/3.5). The productfractions were collected and the solvent was evaporated to dryness,yielding 1.8 g of intermediate 12 (used as such in the next reactionstep).

d) Preparation of 6-quinazolinol,4-[[5-chloro-2-[(6-hydroxyhexyl)oxy]phenyl]amino]-7-methoxy-(intermediate 13)

LAH (0.015 mol) was stirred in THF (40 ml) and then a solution ofintermediate 12 (0.0037 mol) in THF (80 ml) was added dropwise under N₂at RT. The reaction mixture was stirred over the weekend, then treatedwith H₂O (0.9 ml), aq. NaOH soln. (15%, 0.9 ml) and H₂O (2.7 ml). Thereaction mixture was filtered, the residue washed and the filtrate wasconcentrated under reduced pressure. The residue was stirred in DIPE andthe solid was collected by filtration, yielding 0.8 g (53%) ofintermediate 13.

EXAMPLE A4 a) Preparation of pentanoic acid,5-(4-chloro-2-nitrophenoxy)-, methyl ester (intermediate 14)

A mixture of 4-chloro-6-nitrophenol (0.023 mol, K₂CO₃ (0.027 mol) andN,N-dimethylformamide (80 ml) was stirred at 50° C. for 30 min., then5-bromo-, methylester pentanoic acid (0.627 mol) was added dropwise endthe reaction mixture was stirred for 18 hours at 50° C. The mixture wasfiltered and the filtrate was neutralised with HCl (1N). This mixturewas poured in ice water and stirred for 30 min. The resultingprecipitate was collected by filtration, washed, re-dissolved inDCM/CH₃OH(95/5) dried (MgSO₄), filtered and concentrated, yielding 6.6 gof intermediate 14 (used as such in the next reaction step).

b) Preparation of pentanoic acid, 5-(2-amino-4-chlorophenoxy)-, methylester (intermediate 15)

A mixture of intermediate 14 (0.023 mol) and ethylamine (1 g) in THF(100 ml) was hydrogenated with Pt/C 5% (2 g) as catalyst in the presenceof DIPE (1 ml). After uptake of H₂ (3 equiv.), the reaction mixture wasover a small plug of Dicalite and the filtrate was concentrated,yielding intermediate 15.

c) Preparation of pentanoic acid,5-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenoxy]-,methyl ester (intermediate 16)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.0067mol) and intermediate 15 (0.0048 mol) in 2-propanol (60 ml) was stirredand heated at 80° C. for 4 hours. The reaction mixture was filtered, thesolid retained was washed and dried 0.7 g. The filtrate was concentratedand the residue (oil) was chromatographed over silica gel (eluent:DCM/CH₃OH 96.5/3.5). The pure fraction were collected and concentrated,yielding 1.5 g of intermediate 16.

d) Preparation of 6-quinazolinol,4-[[5-chloro-2-[(5-hydroxypentyl)oxy]phenyl]amino]-7-methoxy-(intermediate 17)

A mixture of LAH (0.013 mol) in THF (25 m) was stirred at RT under N₂,then a solution of intermediate 16 (0.0032 mol) in THF (45 ml) was addeddropwise and the reaction mixture was stirred overnight. The reactionmixture was treated with water (0.8 ml), NaOH (0.8 ml, 15%) and againwater (2.4 ml) and the mixture was stirred for 15 min. The mixture wasfiltered and the filtrate was concentrated, re-dissolved in DCM/CH₃OH(95/5), neutralised with HCl (1N), concentrated and then purified oversilica gel (eluent: DCM/CH₃OH 91.5/8.5). The product fractions werecollected and concentrated, yielding 0.400 g of intermediate 17.

EXAMPLE A5 a) Preparation of hexanoic acid, 6-(2-nitrophenoxy)-, methylester-(intermediate 18)

A mixture of 2-nitro-phenol (0.014 mol) and K₂CO₃ (0.017 mol) inN,N-dimethylformamide (50 ml) was stirred for 15 min. at 50° C., then6-bromo-hexanoic acid methyl ester (0.017 mol) was added dropwise andthe reaction mixture was stirred for 18 hours at 50° C. The reactionmixture was filtered and poured onto ice water. The resultingprecipitate was filtered, washed and dried, yielding 3.0 g ofintermediate 18 (used as such in the next reaction step).

b) Preparation of hexanoic acid, 6-(2-aminophenoxy)-, methyl ester(intermediate 19)

A mixture of intermediate 18 (0.011 mol) in THF (100 ml) washydrogenated with Pt/C 5% (0.5 g) as a catalyst in the presence of DIPE(0.5 ml). After uptake of H₂ (3 equiv.), the reaction mixture wasfiltered over a small plug of Dicalite and concentrated, yieldingintermediate 19.

c) Preparation of hexanoic acid,6-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]phenoxy]-, methylester (intermediate 20)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.011mol) and intermediate 19 (0.011 mol) in 2-propanol (100 ml) was heatedand stirred at 80° C. for 5 hours. The reaction mixture was concentratedand the residue (oil) was purified over silica gel (eluent: DCM/CH₃OH96.5/3.5). The product fractions were collected and and concentrated,yielding 2.3 g of intermediate 20 (used as such in the next reactionstep).

d) Preparation of 6-quinazolinol,4-[[2-[(6-hydroxyhexyl)oxy]phenyl]amino]-7-methoxy- (intermediate 21)

A mixture of LAH (0.020 mol) in THF (30 ml) was stirred at RT and then asolution of intermediate 20 (0.005 mol) in THF (50 ml) was addeddropwise. The reaction mixture was stirred overnight, treated with H₂O(1 ml), aqueous NaOH soln. (1 ml, 15%) and again with H₂O (3 ml). Thismixture was filtered, the residue was washed and the filtrate wasneutralised with HCl (1N). The filtrate was then concentrated and theresidue was dried (vac.) at 55° C., yielding 0.5 g of intermediate 21.

EXAMPLE A6 a) Preparation of hexanoic acid, 6-(4-bromo-2-nitrophenoxy)-,methyl ester (intermediate 22)

A mixture of 4-bromo-2-nitrophenol (0.046 mol) in DMA (100 ml) washeated to 40° C. and then K₂CO₃ (0.046 mol) was added. The reactionmixture was stirred for 15 min. 6-Bromo-hexanoic acid methyl ester(0.046 mol) was added and the mixture was stirred overnight at 40° C.Extra 6-bromo-hexanoic acid methyl ester (2 g) was added and thereaction mixture was stirred for another 2 hours; The mixture was cooledto RT and poured into ice water (400 ml). The resulting precipitate wasfiltered, dissolved in DCM, dried (MgSO₄) and filtered again. Finally,the filtrate was evaporated, yielding 14.24 g (90%) of intermediate 22.

b) Preparation of hexanoic acid, 6-(2-amino-4-bromophenoxy)-, methylester (intermediate 23)

A mixture of intermediate 22 (0.04 mol) and ethylamine (0.044 mol) inTHF (250 ml) was hydrogenated with Pt/C 5% (2 g) as a catalyst in thepresence of DIPE (2 ml). After uptake of H₂ (3 equiv.), the reactionmixture was filtered over a small plug of Dicalite and concentrated,yielding 12.8 g of intermediate 23 (98%).

c) Preparation of hexanoic acid,6-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-bromophenoxy]-,methyl ester (intermediate 24)

A mixture of 4-chloro-6-acetoxy-7-methoxyquinazoline hydrochloride(0.00554 mol) and intermediate 23 (0.00554 mol) in 2-propanol (10 ml)was heated to 80° C. After 1 hour, the reaction mixture was homogeneousand was coloured black. The mixture was stirred overnight at RT,concentrated and then purified by column chromatography over silica gel.Two product fractions were collected and concentrated. Fraction 2 wasstirred in 2-propanol/DIPE (1/24), filtered and the solid retained wasdried, yielding intermediate 24.

d) Preparation of 6-quinazolinol,4-[[5-bromo-2-[(6-hydroxyhexyl)oxy]phenyl]amino]-7-methoxy-(intermediate 25)

A mixture of intermediate 24 (0.00188 mol) in THF (40 ml) was addeddropwise to a stirred suspension of LAH (0.0075 mol) in THF (20 ml) atRT under N₂-atm., for 16 h. The reaction mixture was subsequentlytreated with H₂O (0.4 ml), and after 15 min with aqueous NaOH soln. (0.4ml, 15%), and finally with H₂O (1.2 ml) (colour change from grey/greento yellow). The reaction mixture was filtered and the filtrate wasneutralised with HCl (1N) and concentrated. The residue was stirred inCH₃CN/DIPE (24/1) and the solid was collected by filtration and dried,yielding intermediate 25.

EXAMPLE A7 a) Preparation of heptanoic acid,7-(4-chloro-2-nitrophenoxy)-, ethyl ester (intermediate 26)

A mixture of 4-chloro-6-nitro-phenol (0.017 mol) and K₂CO₃ (0.019 mol)in DMA (70 ml) was stirred at 50° C. for 15 min., then 6-bromo-,ethylester hexanoic acid (0.019 mol) was added and the reaction mixture wasstirred overnight at 50° C. The resulting precipitate was filtered andthe filtrate was concentrated under reduced pressure, yieldingintermediate 26 (used as such in the next reaction step).

b) Preparation of heptanoic acid, 7-(2-amino-4-chlorophenoxy)-, ethylester (intermediate 27)

A mixture of intermediate 26 (0.017 mol) and dimethyl-amine (1 g) in THF(100 ml) was hydrogenated with Pt/C 50/(2 g) as a catalyst in thepresence of DIPE (1 ml). After uptake of H₂ (3 equiv.), The reactionmixture was filtered over a small plug of Dicalite and concentrated,yielding intermediate 27.

c) Preparation of heptanoic acid,7-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenoxy]-,ethyl ester (intermediate 28)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.0051mol) and intermediate 27. (0.006 mol) in 2-propanol (50 ml) was stirredand heated at 80° C. for 6 hours, then the solvent was evaporated underreduced pressure. The crude residue was purified by columnchromatography over silica gel (eluent: DCM/CH₃OH 97.5/2.5). The productfractions were collected and and concentrated, yielding 2.4 g (92%) ofintermediate 28.

d) Preparation of 6-quinazolinol,4-[[5-chloro-2-[(7-hydroxyheptyl)oxy]phenyl]amino]-7-methoxy-(intermediate 29)

A mixture of LAH (0.0186 mol) in THF (40 ml) was stirred at RT and thena solution of intermediate 28 (0.0047 mol) in THF (40 ml) was addeddropwise. The reaction mixture was stirred for 18 hours and extra LAH(0.0092 mol) was added, then the resulting mixture was stirred foranother 1 day. The reaction mixture was subsequently treated with H₂O(1.5 ml), aq. NaOH soln. (15%, 1.5 ml) and then H₂O (4.5 ml) and themixture was stirred for 10 min. This mixture was filtered and thefiltrate was neutralised with HCl (1N), concentrated and the residue waspurified by column chromatography (silica gel, eluent: DCM/CH₃OH 95/5).The product fractions were collected and concentrated, yielding 0.5 g(25%) of intermediate 29.

EXAMPLE A8 a) Preparation of 1-octanol, 8-(4-chloro-2-nitrophenoxy)-,acetate (ester) (intermediate 30)

A mixture of 4-chloro-6-nitro-phenol (0.0205 mol), fine molecular sieves(3.5 g), DMA, p.a. (50 ml) and K₂CO₃ (0.0238 mol) was stirred for 1hour, then 8-bromo-1-octanol-acetate (0.0235 mol) was added and thereaction mixture was heated at 50° C. for 16 hours. The mixture wascooled and poured out into ice water, then extracted with toluene (2times 150 ml). The organic layers were combined, dried (MgSO₄), filteredoff and the solvent was evaporated (vac.). The residue was purified byColumn chromatography over silica gel (eluent: DCM/Hexane 80/20). Theproduct fractions were collected and the solvent was evaporated,yielding 6.2 g (87.9%) of intermediate 30.

b) Preparation of 1-octanol, 8-(2-amino-4-chlorophenoxy)-, acetate(ester) (intermediate 31)

A mixture of intermediate 30 (0.018 mol) in THF (100 ml) washydrogenated with Pt/C 5% (1 g) as a catalyst in the presence ofthiophene (1 ml) [1178-005). After uptake of H₂ (3 equiv.), the reactionmixture was filtered over a small plug of Dicalite and concentrated,yielding 5.6 g of intermediate 31 (used as such in the next reactionstep).

c) Preparation of 6-quinazolinol,4-[2-[[8-(acetyloxy)octyl]oxy]-5-chlorophenyl]amino]-7-methoxy-, acetate(ester) (intermediate 32)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.01mol) and intermediate 31- (0.01 mol) in 2′-propanol (60 ml) was heatedat 80° for 2 hours and the reaction mixture was cooled, thenconcentrated. DIPE was added and the mixture was stirred for 2 hours.The solids were collected and then dried, yielding 5.0 g of intermediate32.

d) Preparation of 6-quinazolinol,4-[[5-chloro-2-[(8-hydroxyoctyl)oxy]phenyl]amino]-7-methoxy-(intermediate 33)

A mixture of intermediate 32 (0.0094 mol) in methanol (100 ml) washeated at 60° C. Then a solution of K₂CO₃ (0.019 mol) in H₂O (10 ml) wasadded dropwise. The organic solvent was evaporated and the aqueousconcentrate was treated with acetic acid. The resulting precipitate wasfiltered off, washed with H₂O and dried (vac.) at 60° C., yielding 3.7 g(88%) of intermediate 33.

EXAMPLE A9 a) Preparation of 1-nonanol, 9-(4-chloro-2-nitrophenoxy)-,acetate (ester) (intermediate 34)

A mixture of 4-chloro-6-nitro-phenol (0.02 mol), DMA, p.a. (70 ml) andK₂CO₃ (0.0246 mol) was heated at 50° C. for 1 hour and then9-bromo,1-nonanol acetate (0.024 mol) was added. The reaction mixturewas heated over the weekend and poured into ice (250 ml). The solidswere collected by filtration, dissolved in DCM., dried (MgSO₄), filteredand concentrated, yielding 8.6 g of intermediate 34.

b) Preparation of 1-nonanol, 9-(2-amino-4-chlorophenoxy)-, acetate(ester) (intermediate 35)

A mixture of intermediate 34 (0.023 mol) in THF (200 ml) washydrogenated at 50° C. with Pt/C 5% (2 g) as a catalyst in the presenceof thiophene (2 ml). After uptake of H₂ (3 equiv.), the catalyst wasfiltered off and the filtrate was evaporated (vac.) yieldingintermediate 35.

c) Preparation of 6-quinazolinyl,4-[[2-[[9-(acetyloxy)nonyl]oxy]-5-chlorophenyl]amino]-7-methoxy-,acetate (ester) (intermediate 36)

A mixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.00099mol) and intermediate 35 (0.0010 mol) in 2-propanol (15 ml) was heatedat 80° C. for 1.5 hours and then the reaction mixture was concentratedunder a dry N₂-flow. DIPE was added; the solids were collected and thendried. Yielding intermediate 36 (off-white solid) Alternatively amixture of 4-chloro-6-methylcarbonyloxy-7-methoxyquinazoline (0.051 mol)and intermediate 35 (0.0051 mol) in 2-propanol (40 ml) was heated at 80°C. for 4 hours and then the reaction mixture was concentrated under adry N₂-flow. DIPE was added; the solids were collected and then dried,yielding 2.38 g (84.3%) of intermediate 36.

d) Preparation of 6-quinazolinol,4-[[5-chloro-2-[(9-hydroxynonyl)oxy]phenyl]amino]-7-methoxy-(intermediate 37)

K₂CO₃ (0.34 g) was added to a solution of intermediate 36 (0.00437 mol)in methanol (40 ml) and H₂O (8 ml) and after 2 hours the resultingprecipitate was filtered, giving solids (I) and filtrate (I). Filtrate(I) was evaporated and then H₂O was added to the residue (pH: 10).Acetic acid was added until pH: 5-6 and the mixture was stirred for 10min., then the solids were filtered off. These solids and solids (I)were combined in H₂O/CH₃OH (20 ml/100 ml) and then K₂CO₃ (0.380 g) wasadded. The reaction mixture was heated at 60° C. for 30 min. and extraK₂CO₃ (0.400 g) was added, then the resulting mixture was stirredovernight. The solvent was evaporated and the residue was treated withH₂O and acetic acid. The resulting solids were filtered off, washed withCH₃OH and dried in a vacuum oven at 60° C., yielding 1.7 g ofintermediate 37.

EXAMPLE A10 a) Preparation of benzoic acid,5-hydroxy-2-nitro-4-(phenylmethoxy)- (intermediate 38)

KOH (75 g) was added to H₂O (175 ml), stirred at RT.4-benzyloxy-5-methoxy-2-nitro-benzoic acid (0.031 mol;) was addedportionwise and the suspension was heated for 12 hours at 75° C. Thereaction mixture was filtered and the filtrate was acidified with HCl(conc.). The resulting precipitate was filtered off, stirred in DIPE,filtered off and dried, yielding 5.75 g (65%) of intermediate 38.

b) Preparation of benzoic acid, 5-hydroxy-2-nitro-4-(phenylmethoxy),methyl ester (intermediate 39)

A mixture of intermediate 38 (0.020 mol) in thionylchloride (50 ml) wasstirred and refluxed for 2 hours and the solvent was evaporated underreduced pressure. The residue was quenched with methanol (50 ml) and themixture was stirred over the weekend. The solvent was evaporated andthen co-evaporated with toluene, yielding intermediate 39.

c) Preparation of benzoic acid,5-(acetyloxy)-2-nitro-4-(phenylmethoxy)-, methyl ester (intermediate 40)

A mixture of intermediate 39 (0.020 mol) in acetic anhydride (40 ml) andpyridine (6 ml) was heated to 90° C. and the reaction mixture wasstirred for 2 hours. The solvent was evaporated under reduced pressureand the residue was filtered over silica gel (eluent: DCM). The productfractions were collected and the solvent was evaporated, yielding 5.4 g(78%) of intermediate 40.

d) Preparation of benzoic acid;5-(acetyloxy)-2-amino-4-(phenylmethoxy)-, methyl ester (intermediate 41)

A mixture of intermediate 40(0.015 mol) in THF (100 ml) was hydrogenatedwith Pt/C 5% (2 g) as a catalyst in the presence of thiophene solution(1 ml) [H178-032]. After uptake of H₂ (3 equiv.), the catalyst wasfiltered off and the filtrate was evaporated, yielding 4.7 g ofintermediate 41.

e) Preparation of 4(3H)-quinazolinone, 6-hydroxy-7-(phenylmethoxy)-(intermediate 42)

A mixture of intermediate 41 (0.015 mol) and ammonium and formic acid(0.0225 mol) in formamide (50 ml) was heated to 150° C. and the reactionmixture was stirred for 4 hours, then the mixture was allowed to reachRT and poured out into ice-water. The resulting precipitate was filteredoff, washed with H₂O and dried (vac.) at 60° C., yielding 2.9 g (72.5%)of intermediate 42.

f) Preparation of 4(3H)-quinazolinone, 6-(acetyloxy)-7-(phenylmethoxy)-(intermediate 43)

A mixture of intermediate 42 (0.011 mol) in monoacetate1,1-1,1-ethenediol (12 ml) and pyridine (2 ml) was heated to 90° C. andthe reaction mixture was stirred for 3 hours, then the mixture waspoured out into ice-water. The resulting precipitate was filtered off,washed and dried, yielding 3.3 g of (97%) of intermediate 43.

g) Preparation of 6-quinazolinol, 4-chloro-7-(phenylmethoxy)-, acetate(ester) (intermediate 44)

A solution of intermediate 43 (0.0032 mol) and N,N-dimethylformamide(cat. quant.) in thionyl chloride (30 ml) was stirred and refluxed for 6hours and then the solvent was evaporated under reduced pressure andco-evaporated with toluene. The residue was dissolved in DCM and washedwith NaHCO₃. The organic layer was separated, dried (MgSO₄), filteredoff and the solvent was evaporated. The residue was used as such in thenext reaction step, yielding 0.6 g (60 to) of intermediate 44.

h) Preparation of 1-hexanol, 6-(4-bromo-2-nitrophenoxy)-, acetate(ester) (intermediate 44a)

A stirring solution of 4-bromo-2-nitrophenol (0.115 mol) in DMA (250 ml)was heated at 40° C., then K₂CO₃ (0.1-15 mol) was added and the reactionmixture was stirred for 15 min. 6-bromo-1-hexanol, acetate (0.115 mol)was added and the mixture was stirred overnight at 40° C. Extra6-bromo-1-hexanol, acetate (4 g) was added, then the resulting mixturewas stirred for 2 hours, cooled to RT and stirred overnight. The mixturewas filtered off and the filtrate was poured out into ice-water (2000ml) and then extracted with EtOAc. The organic layer was separated,dried (MgSO₄), filtered off and the solvent was evaporated under reducedpressure, yielding 39.6 g of intermediate 44a.

i) Preparation of 1-hexanol, 6-(2-amino-4-bromophenoxy)-, acetate(ester) (intermediate 45)

A mixture of intermediate 44a (0.105 mol) in THF (250 ml) washydrogenated with Pt/C 5% (3 g) as a catalyst in the presence ofthiophene solution (3 ml). After uptake of H₂ (3 equiv.), the catalystwas filtered off and the filtrate was evaporated under reduced pressure.The residue was dissolved in DIPE and converted into the hydrochloricacid salt (1:1) with HCl (20 ml, 6N in 2-propanol). The resultingprecipitate was filtered off, washed and dried, yielding 36.91 g (96%)of intermediate 45.

j) Preparation of 6-quinazolinol,4-[[2-[[6-(acetyloxy)hexyl]oxy]-5-bromophenyl]amino]-7-(phenylmethoxy)-,acetate (ester) (intermediate 46)

A mixture of intermediate 44 (0.0031 mol) and intermediate 45 (0.0031mol) in 2-propanol (50 ml) was heated to 80° C. and the reaction mixturewas stirred for 6 hours, then the mixture was allowed to reach RT andstirred overnight. Finally, the solvent was evaporated under reducedpressure, yielding 1.9 g of intermediate 46.

k) Preparation of 6-quinazolinol,4-[[5-bromo-2-[(6-hydroxyhexyl)oxy]phenyl]amino]-7-(phenylmethoxy)-(intermediate 47)

A solution of intermediate 46 (0.0031 mol) in methanol (25 ml) washeated to 60° C. and a solution of K₂CO₃ (0.0062 mol) in H₂O (2.5 ml)was added, then the reaction mixture was stirred for 18 hours. ExtraK₂CO₃ (0.0031 mol) was added and the mixture was stirred for 3 hours at60° C. The organic solvent (CH₃OH) was evaporated under reduced pressureand the aqueous concentrate was treated with acetic acid. The resultingprecipitate was filtered off, washed and dried (vac.) at 60° C.,yielding 1.4 g (84%) of intermediate 47.

EXAMPLE A11 a) Preparation of 6-quinazolinol,4-[[2-[[6-(acetyloxy)hexyl]oxy]-5-bromophenyl]amino]-, acetate (ester)(intermediate 48)

A mixture of intermediate 45 (0.0045 mol) and 4-chloro-6-quinazolinolacetate (ester) (0.0045 mol) in 2-propanol (50 ml) was heated to 80° C.and the reaction mixture was stirred for 2.5 hours. The solvent wasevaporated under reduced pressure and the residue was used as such inthe next reaction step, yielding intermediate 48.

b) Preparation of 6-quinazolinol,4-[[5-bromo-2-[(6-hydroxyhexyl)oxy]phenyl]amino]- (intermediate 49)

A mixture of intermediate 48 (0.0045 mol) and K₂CO₃ (0.0135 mol) in H₂O(2.5 ml) and methanol (25 ml) was stirred at 60° C. for 16 hours and theorganic solvent was evaporated, then the aqueous concentrate wasextracted with CH₃OH/DCM. The organic layer was separated, dried(MgSO₄), filtered off and the solvent was evaporated. The residue wasdried (vac.) at 60° C. and used as such in the next reaction step,yielding intermediate 49.

EXAMPLE A12 a) Preparation of 1-pentanol,5-[[(4-bromo-2-nitrophenyl)methyl]amino]- (intermediate 50)

A solution of 4-bromo-2-nitro- benzaldehyde, (0.013 mol),5-amino-1-pentanol (0.013 mol) and titanium, tetrakis (2-propanolato)(0.014 mol) in EtOH (15 ml) was stirred at RT for 1 hour, then thereaction mixture was heated to 50° C. and stirred for 30 min. Themixture was cooled to RT and NaBH₄ (0.013 mol) was added, portionwise.The reaction mixture was stirred overnight and then poured out intoice-water (50 ml). The resulting mixture was stirred for 20 min., theformed precipitate was filtered off (giving Filtrate (I)), washed withH₂O and stirred in DCM (to dissolve the product and to remove it fromthe Ti-salt). The mixture was filtered and then the filtrate was dried(MgSO₄) and filtered, finally the solvent was evaporated. Filtrate (I)was evaporated until EtOH was removed and the aqueous concentrate wasextracted 2 times with DCM. The organic layer was separated, driedMgSO₄), filtered off and the solvent was evaporated, yielding 3.8 g(93%) of intermediate 50.

b) Preparation of carbamic acid,[(4-bromo-2-nitrophenyl)methyl](5-hydroxypentyl)-, 1,1-dimethylethylester (intermediate 51)

A solution of intermediate 50 (0.0032 mol) in DMC (20 ml) was stirred atRT and a solution of dicarbonic acid, bis(1,1-dimethylethyl)ester(0.0032 mol) in DMC (5 ml) was added dropwise. The reaction mixture wasstirred for 1 hour at RT and washed 2 times with H₂O. The organic layerwas separated, dried (MgSO₄), filtered off and the solvent wasevaporated, yielding intermediate 51.

c) Preparation of carbamic acid,[5-(acetyloxy)pentyl][(4-bromo-2-nitrophenyl)methyl]-, 1,1-dimethylethylester (intermediate 52)

A solution of intermediate 51 (0.0032 mol) and pyridine (0.032 mol) inacetic anhydride (15 ml) was stirred at RT for 16 hours, then thesolvent was evaporated under reduced pressure and co-evaporated withtoluene. The residue was used as such in the next reaction step,yielding 1.47 g (100%) of intermediate 52.

d) Preparation of carbamic acid,[5-(acetyloxy)pentyl][(2-amino-4-bromophenyl)methyl]-1,1-dimethylethylester (intermediate 53)

A mixture of intermediate 52 (0.0033 mol) in THF (50 ml) washydrogenated with Pt/C 5% (0.5 g) as a catalyst in the presence ofthiophene solution (0.5 ml) [H179-007]. After uptake of H₂ (3 equiv.),the catalyst was filtered off and the filtrate was evaporated, yieldingintermediate 53.

e) Preparation of carbamic acid,[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-bromophenyl]methyl][5-(acetyloxy)pentyl]-,1,1-dimethylethyl ester (intermediate 54)

A mixture of intermediate 53 (0.0028 mol) and 4-chloro-7-methoxy-,acetate 6-quinazolinol (ester) (0.0028 mol) in 2-propanol (50 ml) washeated to 60° C. and the reaction mixture was stirred for 1 hour. Thesolvent was evaporated under reduced pressure and the residue was usedas such in the next reaction step, yielding intermediate 54.

f) Preparation of carbamic acid,[[4-bromo-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]methyl](5-hydroxypentyl)-,1,1-dimethylethyl ester (intermediate 55)

A solution of intermediate 54 (0.0028 mol) in methanol (50 ml) wasstirred at RT and a solution of K₂CO₃ (0.0056 mol) in H₂O (5 ml) wasadded, then the reaction mixture was heated to 60° C. and stirred for 18hours. The organic solvent was removed and the aqueous concentrate wasacidified with acetic acid. The resulting precipitate was filtered off,dissolved in DCM, dried (MgSO₄), filtered and the solvent wasevaporated, yielding 1.2 g of intermediate-55.

EXAMPLE A13 a) Preparation of 6-heptenoic acid,7-(4-bromo-2-nitrophenyl)-, (6E)- (intermediate 56)

A mixture of NaH, 60% (0.026 mol, free from mineral oil) in DMSO, dry(15 ml) was heated to 65° C. and the mixture was stirred for 1.5 hour(until the generation of H₂ stopped), then the suspension (dark green)was cooled to 15° C. and a solution of5-carboxypentyltriphenylphosponium bromide (0.013 mol) in DMSO (10 ml)was added dropwise. The resulting solution (red) was stirred at RT for10 min. and a solution of 4-bromo-2-nitro-benzaldehyde (0.013 mol;4-Bromo-2-nitrobenzaldehyde) in DMSO, dry (8 ml) was added rapidly. Thesolution (dark brown) was stirred for 105 min. and quenched withH₂O/Et₂O (2575, 100 ml). The Et₂O-layer was removed and the aqueouslayer was extracted 2 times with ethylacetate, then acidified (pH: 1-2)with HCl (37%) and extracted again with ethylacetate. The organic layerwas separated, dried (MgSO₄), filtered off and the solvent wasevaporated, yielding intermediate 56.

b) Preparation of 6-heptenoic acid, 7-(4-bromo-2-nitrophenyl)-, methylester, (6E)- (intermediate 57)

A solution of intermediate 56 (0.013 mol) in concentrated HCl (0.20 ml)and methanol (10 ml) was stirred overnight at RT and then the solventwas evaporated under reduced pressure. The residue was dissolved in DCMand washed with a NaHCO₃ soln. The organic layer was separated, dried(MgSO₄), filtered off and the solvent was evaporated. The residue wasfiltered over silica gel (eluent: DCM); the product fractions werecollected and the solvent was evaporated, yielding 0.800 g ofintermediate 57.

c) Preparation of benzeneheptanoic acid, 2-amino-4-bromo-, methyl ester(intermediate 58)

A mixture of intermediate 57 (0.0023 mol) in THF (50 ml) washydrogenated with 5% concentrated Pt/C 5% (0.5 g) as a catalyst in thepresence of thiophene solution (0.5 ml) [H179-035]. After uptake of H₂(4 equiv.), the catalyst was filtered off and the filtrate wasevaporated, yielding 0.72 g of intermediate 58.

d) Preparation of benzeneheptanoic acid,2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-bromo-, methyl ester(intermediate 59)

A mixture of intermediate 58 (0.0023 mol) and4-chloro-7-methoxy-6-quinazolinol acetate (ester) (0.0023 mol) in2-propanol (40 ml) was heated to 80° C. and stirred for 4 hours, thenthe solvent was evaporated under reduced pressure. The residue wasstirred in CH₃OH/DIPE (1/9); the resulting precipitate was filtered off,washed with DIPE and dried (vac.) it 60° C., yielding 0.55 g ofintermediate 59.

e) Preparation of 6-quinazolinol,4-[[5-bromo-2-(7-hydroxyheptyl)phenyl]amino]-7-methoxy- (intermediate60)

A mixture of LAH (0.005 mol) in 2-propanol (20 ml) was stirred at RT. Asolution of intermediate 59 (0.001 mol) in 2-propanol (30 ml) was addeddropwise, then the reaction mixture was stirred overnight. Ethylacetate.(20 ml) was added and the excess of 4-chloro-7-methoxy-6-quinazolinolacetate (ester) was decomposed with a 10% HCl soln. (5 ml). The organiclayer was separated, dried (MgSO₄), filtered off and the solvent wasevaporated. The residue was used as such in the next reaction step,yielding intermediate 60.

EXAMPLE A14 a) Preparation of 1-pentanol,5-[[(4-bromo-2-nitrophenyl)methyl]methylamino](intermediate 61)

A solution of intermediate 50 (0.0047 mol), formaldehyde (0.025 mol) andtitanium, tetrakis (2-propanolato) (0.0051 mol) in EtOH (150 ml) washeated to 50° C. and stirred for 1 hour, then NaBH₄ (0.026 mol) wasadded portionwise at RT. The reaction mixture was stirred overnight andthen quenched with water (100 ml). The resulting mixture was stirred for1 hour; the formed precipitate was filtered off and washed. The organicfiltrate was concentrated, then the aqueous concentrate was extractedwith DCM and dried. The solvent was evaporated and the residue wasfiltered over silica gel (eluent: DCM/CH₃OH from 98/2 to 95/5). Theproduct fractions were collected and the solvent was evaporated,yielding 0.5 g of intermediate 61.

b) Preparation of 1-pentanol,5-[[(4-bromo-2-nitrophenyl)methyl]methylamino]-, acetate (ester)(intermediate 62)

A solution of intermediate 61 (0.0015 mol) and pyridine (0.015 mol) inacetic anhydride (8 ml) was stirred overnight at RT, then the solventwas evaporated and co-evaporated with toluene, yielding intermediate 62.

c) Preparation of 1-pentanol,5-[[(2-amino-4-bromophenyl)methyl]methylamino]-, acetate (ester)(intermediate 63)

A mixture of intermediate 62 (0.0015 mol) in THF (50 ml) washydrogenated with Pt/C 5% (0.5 g) as a catalyst in the presence ofthiophene solution (0.5 ml) [H179-034]. After uptake of H₂ (3 equiv.),the catalyst was filtered off and the filtrate was evaporated, yielding0.5 g of intermediate. 63.

d) Preparation of 6-quinazolinol,4-[[2-[[[5-(acetyloxy)pentyl]methylamino]methyl]-5-bromophenyl]amino]-7-methoxy-,acetate (ester) (intermediate 64)

A mixture of intermediate 63 (0.0015 mol) and4-chloro-7-methoxy-6-quinazolinol acetate (ester) (0.0015 mol) in2-propanol (30 ml) was heated to 80° C. and the reaction mixture wasstirred for 1 day. The solvent was evaporated under reduced pressure andthe residue was used as such in the next reaction step, yielding 0.83 gof intermediate 64.

e) Preparation of 6-quinazolinol,4-[[5-bromo-2-[[(5-hydroxypentyl)methylamino]methyl]phenyl]amino]-7-methoxy-(intermediate 65)

A solution of intermediate 64 (0.0015 mol) in methanol (25 ml) wasstirred at RT and a solution of K₂CO₃ (0.003 mol) in H₂O (2.5 ml) wasadded, then the reaction mixture was heated to 60° C. and stirred for 18hours. The solvent was evaporated and H₂O (20 ml) was added, then themixture was neutralised with acetic acid and the formed precipitate wasfiltered off. The filtrate was concentrated under reduced pressure andthe concentrate was extracted with DCM, filtered, then dried (MgSO₄) andthe mixture was concentrated under reduced pressure, yielding 0.5 g(70%) of intermediate 65.

EXAMPLE A15 a) Preparation of methanesulfonic acid, trifluoro-,2-(4-chloro-2-nitrophenyl)ethyl ester (intermediate 66)

A mixture of 2-(4-chloro-2-nitrophenyl)-ethanol (0.01 mol) and2,6-di-tert-butylpyridine (0.012 mol) in nitromethane (30 ml) wasstirred under N₂ at 0° C. and a mixture of trifluoromethylsulfonicanhydride (0.011 mol) in nitromethane (10 ml) was added dropwise at 0°C., then the reaction mixture was allowed to reach RT and stirred for 1hour, yielding intermediate 66.

b) Preparation of 1-butanol, 4-[2-(4-chloro-2-nitrophenyl)ethoxy]-,acetate (ester) (intermediate 67)

A mixture of 1-acetoxy-4-hydroxybutane (0.01 mol) in nitromethane (10ml) was added dropwise to intermediate 66 and then the reaction mixturewas stirred for 1 hour at 65° C. The mixture was cooled and water wasadded. The layers were separated and the aqueous layer was extracted 2times with DCM. The organic layers was separated, dried (MgSO₄),filtered-off and the solvent was evaporated. The residue was purified 2times by column chromatography over silica gel (eluent 1: DCM; eluent 2:hexane/EtOAc 90/10). The product fractions were collected and thesolvent evaporated, yielding 0.800 g (25%) of intermediate 67.

c) Preparation of 1-butanol, 4-[2-<2-amino-4-chlorophenyl)ethoxy]-,acetate (ester) (intermediate 68)

A mixture intermediate 67 in dioxane (40 ml) was hydrogenated at 40° C.with Pt/C (0.300 g) as a catalyst in the presence of thiophene solution(0.3 ml). After uptake of H₂ (3 equiv.), the catalyst was filtered offand the filtrate was evaporated, yielding intermediate 68.

d) Preparation of 6-quinazolinol,4-[[2-[2-[4-(acetyloxy)butoxy]ethyl]-5-chlorophenyl]amino]-7-methoxy-,acetate (ester) (intermediate 69)

A mixture 4-chloro-6-acetoxy-7-methoxyquinazoline (0.00040 mol) andintermediate 68 (0.00035 mol) in dioxane (q.s.) was stirred for 3 hoursat 80° C. and then the solvent was evaporated, yielding intermediate 69.

e) Preparation of 6-quinazolinol,4-[[5-chloro-2-[2-(4-hydroxybutoxy)ethyl]phenyl]amino]-7-methoxy-(intermediate 70)

A mixture of intermediate 69 (residue) and K₂CO₃ (0.0144 mol) in H₂O (25ml) and EtOH (25 ml) was stirred over the weekend at RT, then H₂O (150ml) was added and the reaction mixture was extracted 3 times with DCM.The organic layer was separated, dried (MgSO₄), filtered off and thesovent was evaporated. The residue (0.900 g) was purified by HPLC. Theproduct fractions were collected and the solvent was evaporated,yielding 0.300 g of intermediate-70.

EXAMPLE A16 a) Preparation of benzaldehyde, 4-chloro-2-nitro-, oxime(intermediate 71)

A mixture of 4-chloro-2-nitrobenzaldehyde (0.01077 mol) andhydroxylamine hydrochloride (1:1) (0.01184 mol) in pyridine (20 ml) washeated on an oil bath for 2 hours at 80° C. and then the solvent wasevaporated under reduced pressure. The residue was taken up in CH₃OH/DCM(10/90) and the resulting mixture was extracted with 1N HCl and thenwashed with a NaHCO₃ solution and water. The organic layer wasseparated, dried (MgSO₄), filtered off and the solvent was evaporatedunder reduced pressure. The residue was dried (vacuum) at 50° C.,yielding 1.75 g (81%) of intermediate 71.

b) Preparation of benzaldehyde, 4-chloro-2-nitro-,0-[8-(acetyloxy)octyl]oxime (intermediate 72)

K₂CO₃ (0.00887 mol) was added under heavy stirring to a solution ofintermediate 71 (0.00887 mol) in DMSO (25 ml), then 8-bromooctyl acetate(0.00887 mol) was added and the reaction mixture was stirred for 4 hoursat RT. The mixture was heated for 1 hour on an oil bath at 50-60° C. andthen extra 8-bromooctyl acetate. (0.669 g) and K₂CO₃ (0.369 g) wereadded. The reaction mixture was stirred for 4 hours at 50-60° C. andcooled. The mixture was poured out into H₂O/NH₄Cl and extracted withEtOAc. The EtOAc-layer was dried (MgSO₄), filtered off and the solventwas evaporated (vac.). The residual oil (4 g) was purified by columnchromatography over silica gel (eluent: DCM/Hexane 70/30, 80/20, 100/0).The pure product fractions were collected and the solvent was evaporatedunder reduced pressure, yielding 1.34 g of intermediate 72.

c) Preparation of benzaldehyde, 2-amino-4-chloro-,O-[8-(acetyloxy)octyl]oxime (intermediate-73)

A mixture of intermediate 72 (0.0036 mol) in THF (100 ml) washydrogenated overnight under H₂ at RT with Pt/C 5% (0.5 g) as a catalystin the presence of thiophene-solution. (1 ml) and then the reactionmixture was heated overnight at 50° C. After uptake of H₂, the mixturewas filtered and the filtrate was evaporated. The residue was taken upin THF (100 ml) and the reaction mixture was hydrogenated overnight at50° C. with Pt/C 5% (0.3 g) as a catalyst in the presence of thiophenesolution. (0.1 ml). This mixture in THF (100 ml) was hydrogenatedfurther overnight at RT with Pt/C 5% (0.5 g) as a catalyst. After uptakeof H₂ (3 equiv.), the catalyst was filtered off and the filtrate wasevaporated, yielding intermediate 73.

d) Preparation of benzaldehyde,2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chloro-,O-[8-(acetyloxy)octyl]oxime (intermediate 74)

A mixture of 4-chloro-6-acetoxy-7-methoxyquinazoline (0.0021 mol) andintermediate 73 (0.0022 mol) in 2-propanol, p.a. (30 ml) was heated for1 hour on an oil bath at 80° C. and then the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:DCM/CH₃OH 99.5/0.5 to gradient with CH₃OH). The pure fractions werecollected and the solvent was evaporated, yielding 0.300 g ofintermediate 74.

e) Preparation of benzaldehyde,4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]-,O-(8-hydroxyoctyl)oxime (intermediate 75)

A mixture of intermediate 74 (0.00026 mol) in CH₃OH (10 ml) was treatedwith a mixture of K₂CO₃ (0.0011 mol) in H₂O (1 ml) and then the reactionmixture was stirred overnight at RT. The organic solvent (CH₃OH) wasevaporated and the aqueous concentrate as diluted with H₂O (30 ml). Theresulting mixture was acidified with acetic acid until pH: 4-5, then themixture was stirred for 1 hour and filtered. The obtained solid waswashed with CH₃OH (5 ml) and dried in a vacuum oven at 60° C., yielding0.199 g (78%) of intermediate 75.

EXAMPLE A17 a) Preparation of 1-octanol, 8-(3-nitrophenoxy)-, acetate(ester) (intermediate 76)

A mixture of 3-nitrophenol (0.0144 mol) and K₂CO₃ (0.0144 mol) in2-propanone (20 ml) was stirred for 2.5 hours at RT and then8-bromooctyl acetate (0.0144 mol) was added. The reaction mixture wasstirred for 3 hours at RT and was then stirred and refluxed for 18hours. Extra 8-bromooctyl acetate (0.004 mol) was added and then theresulting mixture was stirred and refluxed for 18 hours. The mixture wascooled to RT, filtered and the filter residue was washed with2-propanone. The filtrates were combined and concentrated under reducedpressure. The concentrate was then purified by column chromatography(eluent: Hexane/EtOAc 85/15). The product fractions were collected andthe solvent was evaporated, yielding intermediate 76.

b) Preparation of 1-octanol, 8-(3-aminophenoxy)-, acetate (ester)(intermediate 77)

A mixture of intermediate 76 (9.0123 mol) in THF (50 ml), washydrogenated at 50° C. with Pt/C 5% (2 g) as a catalyst in the presenceof thiophene solution. (1 ml). After uptake of H₂ (3 equiv.), thecatalyst was filtered off and the filtrate was evaporated, yielding 3.6g of intermediate 77.

c) Preparation of 6-quinazolinol,4-[[3-[[8-(acetyloxy)octyl]oxy]phenyl]amino]-7-methoxy-, acetate (ester)(intermediate 78)

A mixture of intermediate 77 (0.0123 mol) and4-chloro-6-acetoxy-7-methoxyquinazoline (0.0123 mol) in 2-propanol (50ml) was heated at 85° C. until complete dissolution and then thereaction mixture was cooled to RT. The resulting precipitate wasfiltered off, washed with DIPE and dried (vacuum), yielding 5.33 g (88%)of intermediate 78.

d) Preparation of 6-quinazolinol,4-[[3-[(8-hydroxyoctyl)oxy]phenyl]amino]-7-methoxy- (intermediate 79)

A mixture of intermediate 78 (0.00404 mol) and K₂CO₃ (0.00807 mol) inH₂O (8 ml) and CH₃OH (80 ml) was heated at 65° C. for 18 hours and thenthe organic solvent was evaporated under reduced pressure. The residuewas diluted with H₂O and the resulting mixture was acidified with 1N HClto pH: 4. The precipitate was filtered off and dried (vacuum), yielding1.5 g (90%) of intermediate 79.

EXAMPLE A18 a) Preparation of 2-propenamide,3-(4-chloro-2-nitrophenyl)-N-(3-hydroxypropyl)-, (intermediate 80)

1,1′-carbonylbis- 1H-imidazole (0.009 mol) was added to a mixture of4-chloro-2--nitro-cinnamic acid (0.006 mol) in THF (100 ml) at RT andthe resulting mixture was stirred for 2 hours at RT, giving Mixture (I).Mixture (I) was added portionwise to a mixture of 3-amino-1-propanol(0.06 mol) in THF (100 ml) and the reaction mixture was stirred for 2hours at RT. The solvent was evaporated and the residue was taken up inwater (100 ml). The aqueous layer was extracted with DCM (3 times-100ml), then the organic layers were combined, dried and filtered. Thesolvent was evaporated under reduced pressure (several co-evaporationswith toluene were required). The residue was stirred overnight intoluene at RT and the resulting precipitate was filtered off, thenpurified by column chromatography over silica gel (eluent: DCM/CH₃OH100/0 to 97/3). The product fractions were collected and the solvent wasevaporated, yielding 1 g (59%) of intermediate 80.

b) Preparation of 2-propenamide,N-[3-(acetyloxy)propyl]-3-(4-chloro-2-nitrophenyl)- (intermediate 81)

Pyridine (0.035 mol) was added dropwise to a mixture of intermediate 80(0.0035 mol) in acetic anhydride (20 ml) at RT and then the reactionmixture was stirred for 1 hour at RT. Finally, the solvent wasevaporated under reduced pressure, yielding 1.1 g (100%) of intermediate81.

c) Preparation of benzenepropanamide,N-[3-(acetyloxy)propyl]-2-amino-4-chloro- (intermediate 82)

A mixture of intermediate 81 (0.0033 mol) in THF (50 ml) washydrogenated at RT for 10 days with Pt/C 5% (0.5 g) as a catalyst in thepresence of thiophene solution (0.5 ml). After uptake of H₂ (4 equiv.),the catalyst was filtered off and the filtrate was evaporated underreduced pressure. The residue was purified by column chromatography oversilica gel (eluent: DCM/CH₃OH 99.5/0.5 to 95/5). The product, fractionswere collected and the solvent was evaporated under reduced pressure,yielding 0.8 g (81%) of intermediate 82.

d) Preparation of benzenepropanamide,2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-N-[3-(acetyloxy)propyl]-4-chloro-(intermediate 83)

A mixture of intermediate 82 (0.0027 mol) and4-chloro-6-acetoxy-7-methoxyquinazoline (0.0027 mol) in 2-propanol (50ml) was stirred and refluxed for 2 hours and then the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica gel (eluent: DCM/CH₃OH 99/1 to 90/10). Theproduct fractions were collected and the solvent was evaporated underreduced pressure, yielding 0.91 g (65%) of intermediate 83.

e) Preparation of benzenepropanamide,4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]-N-(3-hydroxypropyl)-(intermediate 84)

A mixture of intermediate 83 (0.0017 mol) and potassium carbonate(0.0072 mol) in methanol (20 ml) and water (2 ml) was stirred for 1 hourat RT and then the solvent was evaporated under reduced pressure. Theresidue was taken up in water and the aqueous layer was acidified withacetic acid. The resulting precipitate was filtered off and dried,yielding 0.46 g (63%) of intermediate 84.

EXAMPLE A19 a) Preparation of 6-quinazolinol, 4-chloro-7-methoxy-,acetate (ester) (intermediate 85)

A mixture of 6-(acetyloxy)-7-methoxy-4(1H)-quinazolinone (0.23 mol) andDMF (1 ml) in thionyl chloride (500 ml) was stirred and refluxed for 5hours and then the reaction mixture was cooled to RT. The solvent wasevaporated under reduced pressure and then co-evaporated with toluene.The residue was dissolved in DCM and washed with a saturated aqueousNaHCO₃ solution. The organic layer was separated, dried (MgSO₄),filtered off and the solvent was evaporated under reduced pressure. Theresidue was stirred in DIPE and then the resulting precipitate wasfiltered off, yielding 55.4 g (95%) of intermediate 85.

b) Preparation of 6-quinazolinol,4-[(4-chloro-2-hydroxyphenyl)amino]-7-methoxy-6-acetate monohydrochloricacid (intermediate 86)

A mixture of intermediate 85 (0.00696 mol) and 2-amino-5-chloro- phenol(0.00696 mol) in 2-propanol (100 ml) was heated under stirring for 4hours at 85° C. and the reaction mixture was cooled to RT, then theresulting precipitate was filtered off, yielding intermediate 86,isolated as a monohydrochloric acid.

c) Preparation of 6-quinazolinol,4-[[4-chloro-2-[(6-hydroxyhexyl)oxy]phenyl]amino]-7-methoxy-, 6-acetate(intermediate 87)

A solution of intermediate 86 (0.00076 mol) in DMA (20 ml) was stirredat RT and sodium hydride (0.00091 mol) was added portionwise, then themixture was stirred for 30 min. and a solution of 6-bromo-1-hexanol(0.00091 mol) in DMA (2 ml) was added dropwise. The reaction mixture wasstirred overnight at RT and an aqueous NH₄Cl solution (1 ml) was added.The reaction mixture was poured out into ice water and the solvent wasevaporated. The residue was purified by HPLC and then the productfractions were collected and the solvent was evaporated, yielding 0.030g of intermediate 87.

EXAMPLE A20 Preparation of boronic acid,(8,9,10,11,12,13-hexahydro-26-methoxy-4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecin-17-yl)-(intermediate88)

A mixture of compound 6(0.0006 mol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.00066mol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (0.024 g),potassium acetate (0.00092 mol) and [1,1′-biphenyl]-2-yldicyclohexyl-phosphine (0.024 g) in DMSO (5 ml) was stirred at 80° C. for 2 hours,then the reaction mixture was poured out into ice-water and was stirredfor 1 hour. The resulting precipitate was filtered off and then purifiedby column chromatography (eluent: DCM/CH₃OH from 98/2 to 90/10). Thepure fractions were collected and the solvent was evaporated, yielding0.080 g (33%) of intermediate 88.

EXAMPLE A21 a) Preparation of 1-pentanol,5-[[(4-chloro-5-fluoro-2-nitrophenyl)methyl]amino](intermediate 89)

A solution of 4-chloro-5-fluoro-2-nitro-benzaldehyde (0.0098 mol),pentanolamine (0.0098 mol) and tetrakis (2-propanolato) titanium, (0.011mol) EtOH (10 ml) was stirred for 1 hour at RT and sodium hydroborate(0.615-mol) was added portionwise, then the reaction mixture was stirredovernight at RT and H₂O was added. The mixture was stirred for 15 min.and the precipitate was filtered off. The filtrate was evaporated andthen the residue was dissolved in DCM and washed with H₂O. The organiclayer was separated, dried (MgSO₄), filtered off and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel. The product fractions were collected and the solvent wasevaporated, yielding 2.3 g (48%) of intermediate 89.

b) Preparation of carbamic acid,[5-(acetyloxy)pentyl][(4-chloro-5-fluoro-2-nitrophenyl)methyl]-,1,1-dimethylethyl ester (intermediate 90)

A solution of intermediate 89 (0.0079 mol) in DCM (20 ml) was treatedfor 30 min. with a solution of tert-butoxycarbonyl anhydride (0.082 mol)in DCM (20 ml) and then the reaction mixture was washed with H₂O (2×20ml). The organic layer was separated, dried (MgSO₄), filtered off andthe solvent was evaporated. The residue was dissolved in aceticanhydride (30 ml) and then the solution was treated with pyridine (5 ml)and stirred over the weekend. The solvent was evaporated andco-evaporated with toluene. The residue was purified by columnchromatography over silica gel (eluent: DCM). The product fractions werecollected and the solvent was evaporated, yielding 1.4 g (40.9%) ofintermediate 90.

c) Preparation of carbamic acid,[5-(acetyloxy)pentyl][(2-amino-4-chloro-5-fluorophenyl)methyl]-,1,1-dimethylethyl ester (intermediate 91)

A mixture of intermediate 90 (0.0016 mol); Pe (0.009 mol) and NH₄Cl(0.016 mol) in toluene (40 ml), CH₃OH (40 ml) and H₂O (2 ml) was stirredand refluxed for 2 hours, then the reaction mixture was cooled andfiltered over dicalite. The filtrate was evaporated and then the residuewas diluted with DCM (50 ml), and washed with H₂O. The organic layer wasseparated, dried (MgSO₄), filtered off and the solvent was evaporated,yielding 0.513 g (80%) of intermediate 91.

d) Preparation of carbamic acid,[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chloro-5-fluorophenyl]methyl][5-(acetyloxy)pentyl]-,1,1-dimethylethyl ester (intermediate 92)

A mixture of intermediate 91 (0.000379 mol) and4-chloro-6-acetoxy-7-methoxyquinazoline (0.000379 mol) in 2-propanol (10ml) was heated on an oil bath for 3-hours at 80° C. and then the solventwas evaporated. The residue was purified by column chromatography oversilica gel (gradient eluent: DCM/CH₃OH 100/0 to 99/1). The productfractions were collected and the solvent was evaporated, yielding 0.148g 63%) of intermediate 92.

e) Preparation of carbamic acid,[[4-chloro-5-fluoro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]methyl](5-hydroxypentyl)-,1,1-dimethylethyl ester (intermediate 93)

A solution of intermediate 92 (0.000239 mol) in CH₃OH (10 ml) wastreated with a solution of K₂CO₃ (0.00051 mol) in H₂O (1 ml). Thereaction mixture was stirred overnight, then the mixture was neutralizedwith acetic acid and the solvent was evaporated. The residue was dilutedwith DCM and washed with H₂O. The organic layer was separated, dried(MgSO₄), filtered off and the solvent was evaporated, yielding 0.120 g(93,7%) of intermediate 93.

EXAMPLE A22 a) Preparation of 1-butanol,4-[[2-(4-chloro-2-nitrophenyl)ethyl]amino](intermediate 94)

1-amino-4-butanol (0.0300 mol) was added to a stirred suspension of2-propanol (30 ml) and molecular sieves (8 g) under N₂ at RT and then amixture of 4-chloro-2-nitro-benzeneacetaldehyde (0.0100 mol) in2-propanol (10 ml) was added dropwise. The mixture was stirred for 90min. and sodium cyanotrihydroborate (0.120 mol) was added portionwise(generation of gas). The reaction mixture was stirred overnight andacidified with 6N HCl to pH<2. A saturated aqueous K₂CO₃ solution wasadded to pH: 10 and the resulting mixture was filtered over dicalite.The residual fraction was washed with 2-propanol and stirred in hotEtOAc, then this mixture was filtered over dicante and the filtrate wasevaporated under reduced pressure. The residue was taken up in EtOAc andthe mixture was extracted with 1N HCl (250 ml), then the layers wereseparated to give an aqueous layer (*) and an organic layer (1).

(*) Aqueous layer was separated, neutralized with K₂CO₃ and extractedwith EtOAc. The organic layer was separated, dried, (MgSO₄), filteredoff and the solvent was evaporated, under reduced pressure, yieldingintermediate 94. (fraction 1).

Organic layer (1) was dried (MgSO₄), filtered off and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica gel. The product fractions were collected andthe solvent was evaporated yielding intermediate 94. (fraction 2) Theproduct fractions were collected (Yield 100%).

b) Preparation of carbamic acid, [2-(4-chloro-2-nitrophenyl)ethyl](4-hydroxybutyl)-, 1,1-dimethylethyl ester (intermediate 95)

A mixture of intermediate 94 (0.0015 mol) in DCM (10 ml) was stirred atRT and a solution of bis(1,1-dimethylethyl) dicarbonate (0.0015 mol) inDCM (5 ml) was added dropwise, then the reaction mixture was stirred for1 hour and an extra solution of bis(1,1-dimethylethyl) dicarbonate(0.0015 mol) in DCM (5 ml) was added. The resulting mixture was stirredfor 1 hour and washed 2 times with water. The organic layer wasseparated, dried (MgSO₄), filtered off and the solvent was evaporated,yielding 0.56 g of intermediate 95.

c) Preparation of carbamic acid,[4-(acetyloxy)butyl][2-(4-chloro-2-nitrophenyl)ethyl]-,1,1-dimethylethyl ester (intermediate 96)

A solution of intermediate 95 (0.0015 mol) and pyridine (0.015 mol) inacetic] anhydride (10 ml) was stirred for 18 hours at RT, then thesolvent was evaporated under reduced pressure and co-evaporated withtoluene. The residue was purified over silica gel (eluent: DCM/CH₃OH100/0 to 98/2). The product fractions were collected and the solvent wasevaporated, yielding 0.2 g (33%) of intermediate 96.

d) Preparation of carbamic acid,[4-(acetyloxy)butyl][2-(2-amino-4-chlorophenyl)ethyl]-,1,1-dimethylethyl ester (intermediate 97)

A mixture of intermediate 96 (0.0005 mol) in THF (40 ml) washydrogenated with Pt/C 5% (0.1 g) as a catalyst in the presence ofthiophene solution. (0.1 ml). After uptake of H₂ (3 equiv.), thecatalyst was filtered off and the filtrate was evaporated, yielding(quantitive yield) intermediate 97.

e) Preparation of carbamic acid,[4-(acetyloxy)butyl][2-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]ethyl]-1-dimethylethylester (intermediate 98)

A solution of intermediate 97 (0.0005 mol) and4-chloro-6-acetoxy-7-methoxyquinazoline (0.0005 mol) in 2-propanol (15ml) was stirred for 2 hours at 80° C. and then the solvent wasevaporated under reduced pressure. The crude residue was purified byFlash column chromatography ever silica gel (eluent: DCM/CH₁₃—OH99.8/0.2 to 96/4). The product fractions were collected and the solventwas evaporated yielding 0.150 g of intermediate 98.

f) Preparation of carbamic acid,[2-[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]ethyl](4-hydroxybutyl)-,1,1-dimethylethyl ester (intermediate 99)

A mixture of intermediate 98 (0.00025 mol) and K₂CO₃ (0.0005 mol) inmethanol (20 ml) and water (2 ml) was heated and stirred for 18 hours at50° C. and then the solvent was evaporated under reduced pressure. Theaqueous layer was neutralised with acetic acid and the product wasextracted with DCM. The extract was washed with water, dried (MgSO₄) andfiltered off and then the filtrate was evaporated, yielding 0.130 g ofintermediate 99.

EXAMPLE A23 a) Preparation of benzene,4-chloro-1—(3-chloropropoxy)-2-nitro- (intermediate 100)

Potassium carbonate (0.15 mol) was added portionwise to a mixture of4-chloro-2-nitrophenol (0.1 mol) in 2-propanone (500 ml) at RT. Themixture was stirred and refluxed for 30 min. 1-bromo-3-chloro- propane(0.11 mol) was added dropwise and then the reaction mixture was stirredand refluxed for 45 min. Extra 1-bromo-3-chloro- propane (0.44 mol) wasadded, followed by potassium iodide (1 g) and then the reaction mixturewas stirred and refluxed overnight. The obtained mixture was filteredand the filter residue was washed with 2-propanone. The filtrate wasevaporated under reduced pressure and the residue was purified by columnchromatography over silica gel (eluent: hexane/EtOAc 80/20). The productfractions were collected and the solvent was evaporated, yielding 17.30g (69%) of intermediate 100.

b) Preparation of ethanol,2-[[3-(4-chloro-2-nitrophenoxy)propyl][2-(4-morpholinyl)ethyl]amino]-(intermediate 101)

A mixture of 2-(2-morpholinoethylamino)- ethanol (0.0083 mol),intermediate 100 (0.0085 mol) and sodium carbonate (0.016 mol) inacetonitrile (150 ml) was stirred at reflux temperature for 92 hours andthe reaction mixture was filtered off. The filtrate was evaporated underreduced pressure and the residue was purified over silica gel (eluent:DCM/(CH₃OH/NH₃) 99/1 to 95/5). The product fractions were collected andthe solvent was evaporated under reduced pressure, yielding 1.4 g (44%)of intermediate 101.

c) Preparation of ethanol,2-[[3-(4-chloro-2-nitrophenoxy)propyl][2-(4-morpholinyl)ethyl]amino]-,acetate (ester) (intermediate 102)

Pyridine (0.036 mol) was added to a mixture of intermediate 101 (0.0036mol) in acetic anhydride (25 ml) at RT and then the reaction mixture Gasstirred for 1 hour at RT. Finally, the solvent was evaporated underreduced pressure, yielding 1.6 g (100%) of intermediate 102.

d) Preparation of ethanol,2-[[3-(2-amino-4-chlorophenoxy)propyl][2-(4-morpholinyl)ethyl]amino]-,acetate (ester) (intermediate 103)

A mixture of intermediate 102 (0.0037 mol) in THF (50 ml) washydrogenated at 50° C. with Pt/C 5% (0.5 g) as a catalyst in thepresence of thiophene solution (0.5 ml). After uptake of H₂ (3 equiv.),the catalyst was filtered off and the filtrate was evaporated underreduced pressure. The residue was purified by column chromatography oversilica gel (eluent: DCM/CH₃OH 96/4) The product fractions were collectedand the solvent was evaporated under reduced pressure, yielding 0.88 g(60%) of intermediate 103.

e) Preparation of 6-quinazolinol,4-[[2-[3-[[2-(acetyloxy)ethyl][2-(4-morpholinyl)ethyl]amino]propoxy]-5-chlorophenyl]amino]-7-methoxy-,acetate (ester) (intermediate 104)

A mixture of intermediate 103 (0.0021 mol and4-chloro-6-acetoxy-7-methoxyquinazoline (0.0021 mol) in 2-propanol (100ml) was stirred at reflux temperature for 4 hours and DIPEA (0.3 ml) wasadded, then the reaction mixture was stirred and refluxed for 2 hours.Finally, the solvent was evaporated under reduced pressure, to giveresidue (I). A mixture of residue (I) (max. 0.0021 mol),tris[α-[(1,2-α:4,5-α)-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one]]di-palladium (=Pd₂(DBA)₃) (0.00013 mol),[1,1′-binaphthalene]-2,2′-diylbis[diphenyl- phosphine (=BINAP) (0.00026mol) and calcium oxide (0.021 mol) in dioxane (40 ml) was stirred in asealed tube at 130° C. for 16 hours and then the reaction mixture wasfiltered over dicalite. The filtrate was evaporated under reducedpressure and the residue was purified by column chromatography oversilica gel (eluent: DCM/CH₃OH 98/2 to 90/10). The product fractions werecollected and the solvent was evaporated under reduced pressure,yielding 0.480 g (37%) of intermediate 104.

f) Preparation of 6-quinazolinol,4-[[5-chloro-2-[3-[(2-hydroxyethyl)[2-(4-morpholinyl)ethyl]amino]propoxy]phenyl]amino]-7-methoxy-(intermediate 105)

A mixture of intermediate 104 (0.00073 mol) and potassium carbonate(0.0057 mol) in methanol (20 ml) and water (2 ml) was stirred for 16hours at RT, then the solvent was evaporated under reduced pressure andthe residue was taken up in water. The aqueous layer was washed withDCM, acidified with acetic acid until pH: 7 and extracted with DCM. Theorganic layer was dried (MgSO₄), filtered off and the solvent wasevaporated, yielding 0.250 g (64%) of intermediate 105.

EXAMPLE A24 a) Preparation of benzamide,4-chloro-N-(6-hydroxyhexyl)-2-nitro- (intermediate 106)

1,1′-carbonylbis-1H-imidazole (0.01 mol) was added portionwise to amixture of 4-chloro-2-nitrobenzoic acid (0.01 mol) in DCM (40 ml) at RTand the mixture was stirred for 1 hour at RT, then 6-hydroxyhexylamine(0.01 mol) was added dropwise at RT and the reaction mixture was stirredfor 1 hour at RT. The mixture was washed with water (40 ml) and with.HCl (1N, 40 ml). The organic layer was separated, dried, filtered offand the solvent was evaporated under reduced pressure, yielding 1.7 g(57%) of intermediate 106.

b) Preparation of benzamide,N-[6-(acetyloxy)-hexyl]-4-chloro-2-nitro-(intermediate 107)

Pyridine (0.057 mol) was added dropwise to a mixture of intermediate 106(0.0057 mol) in acetic anhydride (26.7 ml) at RT and then the reactionmixture was stirred for 1 hour at RT. The solvent was evaporated underreduced pressure and the residue was taken up in water, then the mixturewas extracted with toluene. The organic layer was separated, dried,filtered off and the solvent was evaporated under reduced pressure,yielding 1.8 g (92%) of intermediate 107.

c) Preparation of benzamide,N-[6-(acetyloxy)hexyl]-2-amino-4-chloro-(intermediate 108)

A mixture of intermediate 107 (0.0053 mol) in THF (40 ml) washydrogenated at 50° C. with Pt/C (0.5 g) as a catalyst in the presenceof thiophene solution (0.5 ml). Then the reaction mixture was filteredoff and the filtrate was evaporated under reduced pressure. The residuewas hydrogenated again and after uptake of H₂ (3 equiv.), the catalystwas filtered off and the filtrate was evaporated under reduced pressure,yielding 1.56 g (94%) of intermediate 108.

d) Preparation of benzamide,N-[6-(acetyloxy)hexyl]-2-[[6-(acetyloxy)-7-methoxy-4-4-quinazolinyl]amino]-4-chloro-(intermediate 109)

A mixture of intermediate 108 (0.0042 mol) and4-chloro-6-acetoxy-7-methoxyquinazoline (0.0042 mol) in 2-propanol (100ml) was stirred at 50° C. for 16 hours and then the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica gel (eluent: DCM/CH₃OH from 99/1 to 90/10).The pure fractions were collected and the solvent was evaporated,yielding

e) Preparation of benzamide,4-chloro-N-(6-hydroxyhexyl)-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]-(intermediate 110)

Intermediate 109 (0.0023 mol) and potassium carbonate (0.0046 mol) werestirred in water (2 ml) and methanol (20 ml) at 50° C. for 16 hours,then the reaction mixture was concentrated. The residue was acidifiedwith acetic acid and the aqueous layer was extracted with DCM. Theorganic layer was separated, dried, filtered off and the solvent wasevaporated under reduced pressure yielding 0,99 g (97%) of intermediate110.

EXAMPLE A25 a) Preparation of carbamic acid,[(4-bromo-2-nitrophenyl)methyl](5-hydroxypentyl)-, phenylmethyl ester(intermediate 111)

Phenylmethyl chloroformate (0.033 mol) was added dropwise to admixtureof intermediate 50 (max. 0.022 mol) and triethylamine (0.04 mol) in DCM(100 ml) at RT and then the reaction mixture was stirred for 1 hour atRT. Water (100 ml) was adde and the mixture was stirred for 30 min. atRT. The organic layer was separated, dried, filtered off and the solventwas evaporated under reduced pressure. The residue was purified bycolumn chromatography (eluent: DCM/CH₃OH 99.5/0.5). The productfractions were collected and the solvent was evaporated, yielding 6.8 g(68%) of intermediate 111.

b) Preparation of carbamic acid, [(2-amino-4-bromophenyl)methyl](5-hydroxypentyl)-, phenylmethyl ester (intermediate 112)

A mixture of intermediate 111 (0.015 mol) in EtOAc (200 ml) washydrogenated for 40 hours with Pt/C 5% (2 g) as a catalyst in thepresence of thiophene solution (3 ml). After uptake of H₂ (3 equiv.),the catalyst was filtered off and the filtrate was evaporated underreduced pressure, yielding 6.3 g of intermediate 112.

c) Preparation of carbamic acid,[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-bromophenyl]methyl](5-hydroxypentyl)-,phenylmethyl ester HCl (1:1) (intermediate 113)

A solution of 6-acetoxy-4-chloro-7-methoxyquinazoline (0.015 mol) in2-propanol (q.s.) was added to a solution of intermediate 112 (0.015mol) in 2-propanol (q.s.) at 60° C. and then the reaction mixture wasstirred for 1 hour at 70° C. The solvent was evaporated under reducedpressure and the obtained residue was stirred in hexane. The resultingprecipitate was filtered off and dried, yielding 9.35 g (98%) ofintermediate 113, isolated as a hydrochloric salt (1:1).

d) Preparation of carbamic acid, [(2-[[6-acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-bromophenyl]methyl](5-chloropentyl)-,phenylmethyl ester (intermediate 114)

Methanesulfonyl chloride (0.12 mol) was added to a solution ofintermediate 113 (0.0125 mol) in 1-methyl-2-pyrrolidinone (50 ml) at RTand the reaction mixture was stirred for 1 hour at 90° C. The mixturewas poured out into water (300 ml) and the aqueous layer was extractedwith EtOAc (3×100 ml). The organic layer was separated, washed withwater (2×200 ml), dried, filtered off and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by columnchromatography (eluent: DCM/CH₃OH 99.5/0.5 to 94/6). The pure fractionswere collected and the solvent was evaporated under reduced pressure,yielding 3.9 g of intermediate 114.

EXAMPLE A26 a) Preparation of glycine,N-[(4-chloro-2-nitrophenyl)acetyl]-, ethyl ester (intermediate 115)

A slurry of 4-chloro-2-nitro- benzeneacetic acid (0.0051 mol) and1-hydroxy-1H-benzotriazole (0.0051 mol) in DCM (50 ml) was treated with1,1′-carbonylbis-1H-imidazole (0.0051 mol), then after 10 min. DIPEA(0.0051 mol) was added, followed by glycine hydrochloride, ethyl ester(0.0051 mol). The reaction mixture was stirred for 2 hours and waswashed with water (50 ml), with a Na₂CO₃ solution (30 ml) and with 1NHCl. The organic layer was separated, dried (MgSO₄), filtered off andthe solvent was evaporated. DIPE (100 ml) was added to the obtainedresidue and after stirring the resulting solids were collected, yielding1.1 g of intermediate 115.

b) Preparation of glycine, N-[(2-amino-4-chlorophenyl)acetyl]-, ethylester (intermediate 116)

A mixture of intermediate 115 (0.023 mol) in THF (250 ml) washydrogenated with Pt/C (2.0 g) as a catalyst in the presence ofthiophene solution (1 ml). After uptake of H₂ (3 equiv.), the catalystwas filtered off and the filtrate was evaporated. The obtained residuewas suspended in DIPE, then the suspension was stirred at boilingtemperature, cooled and the desired product was collected, yield 6.2 gof intermediate 116.

c) Preparation of glycine,N-[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]acetyl]-,ethyl ester (intermediate 117)

A mixture of intermediate 85 (0.00050 mol) and intermediate 116 (0.00050mol) in 2-propanone (5 ml) was stirred for 16 hours in a pressure tubeat 80° C. oil bath temperature), then the reaction mixture was filteredand the filter residue was air-dried, yielding 0.165 g of intermediate117.

d) Preparation of glycine,N-[[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]acetyl]-,ethyl ester (intermediate 118)

A mixture of intermediate 117 (0.0244 mol) in NH₃/CH₃OH (7N) (50 ml) andCH₃OH (100 ml) was stirred overnight at RT and then the solvent wasevaporated under reduced pressure and at RT. Finally, the obtainedresidue was dried (vac.) overnight at 60° C., yielding 8.2 g (75%) ofintermediate 118.

e) Preparation of glycine,N-[[4-chloro-2-[[6-[3[[(1,1-dimethylethoxy)carbonyl]amino]propoxy]-7-methoxy-4-quinazolinyl]amino]phenyl]acetyl]-,ethyl ester (intermediate 119)

A mixture of intermediate 118 (0.00308 mol) and cesium carbonate (0.0154mol) in DMA (20 ml) was stirred for 1-hour at RT, thenN-(3-bromopropyl)carbamate

(0.00308 mol) was added and the reaction mixture was stirred for 1 hourat RT. Extra N-(3-bromopropyl)carbamate (0.00308 mol) was added and theresulting mixture was stirred overnight. The mixture was filtered andthe filter residue was washed with DMA. The filtrates were combined andconcentrated under reduced pressure. The crude concentrate was purifiedby column chromatography (eluent: DCM/CH₃OH 100/0 to 95/5). The pureproduct fractions were collected and the solvent was evaporated underreduced pressure, yielding intermediate 119.

f) Preparation of glycine,N-[[2-[[6-(3-aminopropoxy)-7-methoxy-4-quinazolinyl]amino]4-chlorophenyl]acetyl]-,ethyl ester (intermediate 120)

A mixture of intermediate 119 (0.003 mol) in TFA (50 ml) and DCM (50 ml)was stirred for 1 hour at RT, then the reaction mixture was concentratedunder reduced pressure and the concentrate was used as such in the nextreaction step without further purification, yielding intermediate 120.

g) Preparation of glycine,N-[[2-[[6-(3-aminopropoxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]acetyl]-(intermediate 121)

A mixture of intermediate 1206(0.003 mol) and LiOH.H₂O (0.018 mol) inethanol (15 ml) and water (1 ml) was stirred for 2 hours and then thisreaction mixture was used as such in the next reaction step withoutfurther purification, yielding intermediate 121.

EXAMPLE A27 a) Preparation of 1-pentanol,5-[[(4-bromo-5-fluoro-2-nitrophenyl)methyl]amino]” (intermediate 122)

Reaction under N₂: a mixture of 4-bromo-5-fluoro-2-nitro- benzaldehyde(0.9379 mol) and 5-amino-1-pentanol (0.0379 mol; 97%) in1,2-dichloro-ethane (150 ml) was stirred for 20 min. and NaBH(OAc)₃(0.0417 mol) was added at RT, then the reaction mixture was stirredovernight at RT (after 2 hours, extra NaBH(OAc)₃ (q.s.) was added). Themixture was washed with a saturated NaHCO₃ solution. The organic layerwas separated, dried (MgSO₄), filtered off and the solvent wasevaporated. The residue was purified by column chromatography (eluent:DCM/(CH₃OH/NH₃) 90/10). The pure product fractions were collected andthe solvent was evaporated, yielding 10.5 of intermediate 122.

b) Preparation of carbamic acid,[(4-bromo-5-fluoro-2-nitrophenyl)methyl](5-hydroxypentyl)-,1,1-dimethylethyl ester (intermediate 123)

A solution of dicarbonic acid, bis(1,11-dimethylethyl)ester (0.034 mol)in DCM (20 ml) was added dropwise to a mixture of intermediate 122(0.031 mol) in DCM (200 ml) and then the resulting mixture was reactedfor 4 hours. The reaction mixture was washed with water and the organiclayer was separated. The organic layer was then dried (MgSO₄), filteredoff and the solvent was evaporated. The residue was purified by columnchromatography (eluent: DCM/CH₃OH 95/5). The product fractions werecollected and then the solvent was evaporated and co-evaporated withtoluene,

yielding 9.8 g of intermediate 123.

c) Preparation of carbamic acid,[(2-amino-4-bromo-5-fluorophenyl)methyl](5-hydroxypentyl)-,1,1-dimethylethyl ester (intermediate 124)

A mixture of intermediate 123 (0.0022 mol) in EtOAc (100 ml) washydrogenated with Pt/C 5% (0.5 g) as a catalyst in the presence ofthiophene solution (q.s.). After uptake of H2 (3 equiv.), the reactionmixture was filtered over dicalite and the filtrate was evaporated. Theresidue was purified by column chromatography (gradient eluent: DCM toDCM/CH₃OH). The pure product fractions were collected and the solventwas evaporated, yielding 0.623 g of intermediate 124.

d) Preparation of carbamic acid,[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-bromo-5-fluorophenyl]methyl](5-hydroxypentyl)-,1,1-dimethylethyl ester (intermediate 125)

A mixture of intermediate 85 (0.00154 mol) in acetonitrile (3 ml) waswarmed to 60° C. and then a solution intermediate 124 (0.00154 mol) inacetonitrile (3 ml) was added dropwise at 6° C. The reaction mixture wasstirred for 30 min. at 60° C. and then cooled to RT. The solvent wasevaporated and the residue was purified by column chromatography overBiotage (gradient eluent: DCM/CH₃OH). The pure product fractions werecollected and the solvent was evaporated, yielding 0.800 g ofintermediate 125.

e) Preparation of carbamic acid,[[4-bromo-5-fluoro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]methyl](5-hydroxypentyl)-,1,1-dimethylethyl ester (intermediate 126)

A solution of potassium carbonate (0.00105 mol) in water (5 ml) wasadded dropwise to a mixture of intermediate 125 (0.00105 mol) inmethanol (50 ml) and then the reaction mixture was stirred for 1 hour atRT. The solvent was evaporated and the residue was extracted with DCM.The organic layer was separated, dried (MgSO₄), filtered off and thesolvent was evaporated. The residue was purified by columnchromatography over Biotage (gradient eluent: DCM/CH₃OH). The pureproduct fractions were collected and the solvent was evaporated,yielding 0.590 g of intermediate 126.

f) Preparation of4,6-ethenopyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine-13(8H)-carboxylicacid, 17-bromo-16-fluoro-9,10,11,12,14,19-hexahydro-20-methoxy-,1,1-dimethylethyl ester (intermediate 127)

A mixture of ADDP (0.00166 mol) in TH dry (70 ml) under N₂ was cooled onan ice bath to 5° C., then tributyl- phosphine (0.00166 mol) was addedand the mixture was stirred for 5 min. at 5° C. A solution ofintermediate 126. (0.00055 mol) in THF dry (10 ml) was slowly addeddropwise and the reaction mixture was stirred for 20 min. at 5° C. andwas then allowed to reach RT. The mixture was stirred for 3 hours at RTand the solvent was evaporated. The residue was purified by columnchromatography (gradient eluent: DCM/CH₃OH). The pure product fractionswere collected and the solvent was evaporated, yielding intermediate127.

EXAMPLE A28 a) Preparation of glycine,N-[[2-[[6-(2-bromoethoxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]acetyl]-,ethyl ester (intermediate 128)

A mixture of intermediate 118 (0.0138 mol) and cesium carbonate (0.0690mol) in DMF (120 ml) was stirred for 30 min. at RT, then1,2-dibromo-ethane (0.117 mol) was added and the reaction mixture wasstirred overnight at RT. The solvent was evaporated under reducedpressure and the residue was co-evaporated with toluene. The obtainedresidue was stirred in DIPE and the desired product was filtered off,yielding 6.93 g (91%) of intermediate 128.

b) Preparation of glycine,N-[[4-chloro-2-[[7-methoxy-6-[2-[[2-(4-morpholinyl)ethyl]amino]ethoxy]4-quinazolinyl]amino]phenyl]acetyl]-,ethyl ester (intermediate 129)

A mixture of intermediate 128 (0.00181 mol) and 4-morpholineethanamine(0.00907 mol) in ethanol (20 ml) was heated in a microwave oven for 90min. at 100° C. and then the reaction mixture was purified by RPhigh-performance liquid chromatography. The product fractions werecollected and the solvent was evaporate yielding 0.39 g (36%) ofintermediate 129.

c) Preparation of glycine,N-[[4-chloro-2-[[7-methoxy-6-[2-[[2-(4-morpholinyl)ethyl]amino]ethoxy]-4-quinazolinyl]amino]phenyl]acetyl]-(intermediate 130)

A mixture of intermediate 129 (0.00065 mol) and LiOH.H₂O (0.0032 mol) inethanol (20 ml) and water (2 ml) was stirred for 2 hours at RT and thenthe solvent was evaporated under reduced pressure, yielding intermediate130 (used as such in the next reaction step without furtherpurification).

EXAMPLE A29 a) Preparation of benzoic acid, 4-fluoro-,5-[(4-fluorobenzoyl)amino]-2-nitrophenyl ester (intermediate 131)

A solution of 5-amino-2-nitro- phenol (0.032 mol) and triethylamine(0.065° mol) in DCM (100 ml) was stirred at RT, then a solution of4-fluoro- benzoyl chloride (0.065 mol) in DCM (10 ml) was added dropwiseand the reaction mixture was stirred for 1 day at RT. The mixture waswashed 2 times with 1N HCl and once with water. The organic layer wasseparated, dried (MgSO₄), filtered off and the solvent was evaporated.The obtained residue was stirred in ethanol/hexane (50/50), filtered offand dried, yielding 5.25 g of intermediate 131.

b) Preparation of benzamide, 4-fluoro-N-(3-hydroxy-4-nitrophenyl)-(intermediate 132)

A mixture of intermediate 131 (0.0132 mol) in methanol (80 ml) wasstirred at RT and then a solution of NaOCH₃ 30% in methanol (0.0132 mol)in methanol (10 ml) was added. The reaction mixture was stirred for 30minutes and the organic solvent was evaporated under reduced pressure.The obtained concentrate was stirred in 1N HCl, then the resultingprecipitate was filtered off, washed with water and dried (vacuum) at60° C., yielding 3.3 g of intermediate 132.

c) Preparation of benzamide,N-[3-[[6-(acetyloxy)hexyl]oxy]-4-nitrophenyl]-4-fluoro- (intermediate133

A mixture of intermediate 132 (0.011 mol) and potassium carbonate (0.012mol) in DMA (100 ml) was stirred for 1 hour at 60° C., then 6-bromohexylacetate (0.012 mol) was added and the reaction mixture was stirred for18 hours at 60° C. Extra 6-bromohexyl acetate (0.300 g) was added andthe mixture was stirred for 5 hours more. The resulting-mixture waspoured out into ice, water and was extracted with EtOAc. The organiclayer was separated, dried (MgSO₄), filtered off and the solvent wasevaporated, yielding 4.6 g of intermediate 133.

Preparation of benzamide,N-[3-[[6-(acetyloxy)hexyl]oxy]-4-aminophenyl]-4-fluoro- (intermediate134)

A mixture of intermediate 133 (0.0024 mol) in methanol (75 ml) in aclosed vessel was hydrogenated overnight at 50° C. with Pd/C 10% (1 g)as a catalyst in the presence of thiophene solution (1 ml). After uptakeof H₂ (3 equiv.), the catalyst was filtered off, to give Filtrate (I). Amixture of intermediate 133 (0.0024 mol) in THF (75 ml) in a closedvessel was hydrogenated overnight at 50° C. with Pd/C 10% (1 g) as acatalyst in the presence of thiophene solution (1 ml). After uptake ofH₂ (3 equiv.), the catalyst was filtered off, to give Filtrate (II).Filtrate (I) and Filtrate (II) were combined and evaporated underreduced pressure, yielding 1.85 g of intermediate

e) Preparation of benzamide,N-[3-[[6-(acetyloxy)hexyl]oxy]-4-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]phenyl]-4-fluoro-(intermediate 135)

A mixture of intermediate 85 (0.0048 mol) and intermediate 134 (0.0048mol) in 2-propanol (80 ml) was stirred for 1 hour at 80-C, then theresulting precipitate was filtered off, washed and dried, yielding 1.15g of intermediate 135.

f) Preparation of benzamide,4-fluoro-N-[3-[(6-hydroxyhexyl)oxy]-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]-(intermediate 136)

A solution of intermediate 135 (0.0019 mol) and potassium carbonate(0.0038 mol) in water (4 ml) and methanol (40 ml) was stirred for 1 hourat 50° C., then a mixture of potassium carbonate (0.26 g) in water (2ml) was added and the reaction mixture was stirred for 4 hours. Thesolvent was evaporated under reduced pressure and the obtained residuewas dissolved in acetic acid (100%). After stirring for 30 min., thesolvent was evaporated and the crude residue was stirred in DCM. Theformed precipitate was filtered off, washed and then stirred in water.The obtained precipitate was filtered off, washed and dried (vacuum) at60° C., yielding 0.650 g (66%) of intermediate 136.

EXAMPLE A30 a) Preparation of alanine,N-[(4-chloro-2-nitrophenyl)acetyl]-2-methyl-, ethyl ester (intermediate137)

A mixture of 4-chloro-2-nitro- benzeneacetic acid (0.00456 mol),1-hydroxy-1H-benzotriazole (0.00456 mol), 1,1′-carbonylbis-1H-imidazole(0.00456 mol) and DIPEA (0.00456 mol) in DCM (20 ml) was stirred at RTfor 15 min., then 2-methyl-alanine, ethyl ester (0.00456 mol) was addedand the reaction mixture was stirred over the weekend at RT. The mixturewas washed 2 times with a saturated potassium carbonate solution, 2times with 1N HCl and once with water. The organic layer was separated,dried (MgSO₄), filtered off and the solvent was evaporated, yieldingintermediate 137.

b) Preparation of alanine, N-[(2-amino-4-chlorophenyl)acetyl]-2-methyl-,ethyl ester (intermediate 138)

A mixture of intermediate 137 (0.00456 mol) in ethanol (25 mol) and THF(25 ml) was hydrogenated at 50° C. with Pt/C 5% (0.5 g) as a catalyst inthe presence of thiophene solution (0.3 ml). After uptake of HE (3equiv.), the catalyst was filtered off and the filtrate was evaporated,yielding 0.65 g of intermediate 338.

c) Preparation of alanine,N-[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]+chlorophenyl]acetyl]-2-methyl-,ethyl ester (intermediate 139)

A mixture of intermediate 138 (0.0022 mol) and intermediate 85 (0.0022mol) in acetonitrile (25 ml) was heated to 80° C. and stirred for 2hours. The solvent was evaporated and the residue was purified by flashcolumn chromatography (eluent: DCM/CH₃OH 100/0, 95/5); then the productfractions were collected and the solvent was evaporated, yielding 0.68 gof intermediate 139.

d) Preparation of alanine,N-[[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]acetyl]-2-methyl-,ethyl ester (intermediate 140)

A mixture of intermediate 139 (0.0013 mol) in CH₃OH/NH₃ (7N) (10 ml) andmethanol (10 ml) was stirred for 18 hours at RT and then the solvent wasevaporated under reduced pressure, yielding 0.600 g of intermediate 140.

e) Preparation of alanine,N-[[4-chloro-2-[[6-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-7-methoxy-4-quinazolinyl]amino]phenyl]acetyl]-2-methyl-,ethyl ester (intermediate 141)

A mixture of intermediate 140 (0.0013 mol) and cesium carbonate (0.0063mol) in DMA (20 ml) was stirred for 45 min. at RT, then (2-bromoethyl)-carbamic acid 1,1-dimethylethyl ester (0.0014 mol) was added and themixture was stirred for 4 hours. Extra (2-bromoethyl)- carbamic acid1,1-dimethylethyl ester (0.0014 mol) was added and the reaction mixturewas stirred overnight at RT. The resulting precipitate was filtered offand the filtrate was evaporated, yielding intermediate 141 (quantitativeyield, used as such in the next reaction step).

f) Preparation of alanine,N-[[2-[[6-(2-aminoethoxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]acetyl]-2-methyl-,ethyl ester (intermediate 142)

A solution of intermediate 141 (0.0013 mol) in TFA (15 ml) and DCM (15ml) was stirred for 1 hour at RT and then the solvent was evaporated,yielding 0.670 g of intermediate 142.

g) Preparation of alanine,N-[[2-[[6-(2-aminoethoxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]acetyl]-2-methyl-(intermediate 143)

A mixture of intermediate 142 (0.0013 mol) and LiOH.H₂O (0.0039 mol) inethanol (20 ml) and water (1 ml) was heated and stirred for 1 hour at40° C., then extra LiOH H₂O (0.01192 mol) was added and the reactionmixture was stirred for 3 hours. Again LiOH.H₂O (0.00477 mol) was addedand the resulting mixture was stirred for 1 hour at 40° C. Finally, thesolvent was evaporated under reduced pressure, yielding intermediate 143(Quantitative Yield).

EXAMPLE A31 a) Preparation of beta-alanine,N-[(2-amino-4-chlorophenyl)methyl]-; methyl ester (intermediate 144)

A mixture of β-Alanine, methyl ester, hydrochloride (0.020 mol),4-chloro-2-nitro-benzaldehyde (0.010 mol) and potassium fluoride (0.019mol) in methanol (100 ml) was hydrogenated at 50° C. for 24 hours withPt/C (1 g, slurry in THF) as a catalyst in the presence of thiophenesolution (1 ml, 4% in 2-propanol). After uptake of H₂ (4 equiv.), thereaction mixture was filtered over dicalite, then the filter residue waswashed with DCM and the solvent was evaporated. The obtained residue wasRedissolved in methanol and was used as such in the next reaction step,yielding intermediate 144.

b) Preparation of beta-alanine,N-[(2-amino-4-chlorophenyl)methyl]-N-[(1,1-dimethylethoxy)carbonyl]-,methyl ester (intermediate 145)

Tert-butyl dicarbonate (0.060 mol) was added to intermediate 144 (0.020mol) and the reaction mixture was stirred for 1 hour, then NH₃/CH₃OH wasadded and the mixture was stirred for 1 hour. The solvent was evaporatedand the dry residue was filtered over silica gel with DCM as eluent. Thefilter residue was purified by RP high-performance liquidchromatography, then the product fractions were collected and thesolvent was evaporated, yielding 1.206 g (36%) of intermediate 145.

c) Preparation of beta-alanine,N-[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chloro-phenyl]methyl]—N-[(1,1-dimethylethoxy)carbonyl]-,methyl ester (intermediate 146)

A solution of intermediate 145 (0.0035 mol) in acetonitrile (40 ml) washeated to 80° C., then intermediate 85 (0.0035° mol) was added and thereaction mixture was stirred for 4 hours at 80° C. Finally, the solventwas evaporated to dryness, yielding intermediate 146 (used as such inthe next reaction step).

d) Preparation of beta-alanine, N-[[4-chloro-2-[(6-hydroxy-7ethoxy-4-quinazolinyl)amino]phenyl]methyl]-N-[(1,1-dimethylethoxy)carbonyl]-,methyl ester (intermediate 147)

NH₃/CH₃OH (7N) (0.035 mol) was added to a solution of intermediate 146(0.0035 mol) in methanol (5 ml) and the reaction mixture was stirred for30 min. at RT. The solvent was evaporated and the obtained residue wasdissolved in methanol. DIPE was added and the resulting precipitate wasfiltered off and dried, yielding 0.9125 g. A second crop could beobtained by adding heptane to the filtrate, yielding 0.8794 g (total:93%) of intermediate 147.

e) Preparation of beta-alanine,N-[[4-chloro-2-[[6-[3-[[(1,1-dimethylethoxy)carbonyl]amino]propoxy]-7-methoxy-4-quinazolinyl]amino]phenyl]methyl]-N-[(1,1-dimethylethoxy)carbonyl]-,methyl ester (intermediate 148)

cesium carbonate (0.00775 mol) was added to a solution of intermediate147(0.001155 mol) in DMF dry (15 ml) and the mixture was stirred for 15min. at RT, then (3-bromopropyl)- carbamic acid 1,1-dimethylethyl ester(0.00155 mol) was added and the reaction mixture was stirred overnightat RT. The solvent was evaporated and the residue was dissolved in DCM.This solution was slowly filtered and the filter residue was washed withDCM, yielding intermediate 148 (used as such in the next reaction step).

f) Preparation of beta-alanine,N-[[2-[[6-(3-aminopropoxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]methyl]-hydroch;oric acid salt (1:1) (intermediate 149)

Water (4 ml) was added to a solution of intermediate 148 (0.00155 mol)in dioxane (10 ml), then hydrochloric acid (4 ml, 36-38%) was added andthe mixture was stirred until the generation of gas stopped. Extrahydrochloric acid (2 ml, 36-38%) was added and the reaction mixture wasstirred in a closed vessel for 8 hours. Finally, the solvent wasevaporated, yielding intermediate 149 (used as such in the next reactionstep).

EXAMPLE A32 a) Preparation of (R)proline,1-[(4-chloro-2-nitrophenyl)methyl]-, 1,1-dimethylethyl ester(intermediate 150)

Tetrakis (2-propanolato) titanium (0.010 mol) was added to a solution ofD-Proline, 1,1-dimethylethyl ester, hydrochloride (0.010 mol) and4-chloro-2-nitro--benzaldehyde (0.010 mol) in DCM (30 ml), then themixture was stirred for 1 hour at RT and NaBH(OAc)₃ (0.011 mol) wasadded. The reaction mixture was stirred for 2 hours at RT and then waterwas added. The mixture was filtered over a P2 glass filter and washedwith DCM, then the organic layer was separated and the aqueous layer wasextracted 2 times with DCM. The organic layers were combined, dried,filtered off and the solvent was evaporated, yielding intermediate 150(used as such in the next reaction step).

b) Preparation of (R) proline, 1-[(2-amino-4-chlorophenyl)methyl]-;1,1-dimethylethyl ester (intermediate 151)

A mixture of intermediate 150 (0.01 mol) in ethanol (100 ml) and THF (50ml) was hydrogenated with Pt/C 5% (1 g) as a catalyst in the presence ofthiophene solution (1 ml: 4% in DIPE). After uptake of H₂ (3-equiv.),the catalyst was filtered off and the filtrate was evaporated. Theresidue was purified by RP high-performance liquid chromatography, thenthe product fractions were collected and the organic solvent wasevaporated. The obtained concentrate was filtered and then the filterresidue was washed with water and dried in an oven, to give 1.0453 g(34%) of intermediate 151. The filter was washed with DCM and theaqueous layer was extracted with DCM. The organic layer was then driedand filtered over potassium carbonate, to give 0.0480 g intermediate151.

c) Preparation of (R)proline,1-[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]methyl]-,1,1-dimethylethyl ester (intermediate; 152)

Intermediate 85 (0.001 mol) was added to a solution of intermediate 151(0.001 mol) in 2-propanol (q.s.) and then the reaction mixture wasstirred for 2 hours and the solvent was evaporated. Extra Intermediate85 (0.0185 g) was added to the previous prepared reaction mixture, thenthe mixture was stirred for one more hour and the solvent wasevaporated, yielding intermediate 152.

d) Preparation of (R)proline,1-[[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]methyl]-,1,1-dimethylethyl ester (intermediate 153)

NH₃/CH₃OH (10 ml) was added to intermediate 152 (0.001 mol) and thereaction mixture was shaken for 1 hour and then the solvent wasevaporated, yielding intermediate 153 (used as such in the next reactionstep).

e) Preparation of (R)proline,1-[[4-chloro-2-[[6-(3-cyanopropoxy)-1-methoxy-4-quinazolinyl]amino]phenyl]methyl]-,1,1-dimethylethyl ester (intermediate 154)

A mixture of intermediate 153 (0.0005 mol), 4-bromo-butanenitrile (0.04ml) and cesium carbonate (0.815 g) was stirred overnight at RT and thenthe reaction mixture was stirred for 30 min at 50° C. Extra4-bromo-butanenitrile (0.009 ml) was added and the mixture was stirredfor 4 hours at RT and for another 15 min. at 50° C. The solvent wasevaporated and the residue was dissolved in DCM. This solution wasfiltered over dicalite and the filtrate was evaporated, yieldingintermediate 154.

f) Preparation of (R)proline,1-[[2-[[6-(4-aminobutoxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]methyl]-,1,1-dimethylethyl ester (intermediate 155)

A mixture of intermediate 154 (0.0005 mol) in CH₃OH/NH₃ (40 ml) washydrogenated at 14° C. with raney nickel (cat. quant.) as a catalyst inthe presence of thiophene solution (0.1 ml). After uptake of H₂ (2equiv.), the catalyst was filtered off and the filtrate was evaporated,yielding intermediate 155.

g) Preparation of (R)proline,1-[[2-[[6-(4-aminobutoxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]methyl]-TFA (1:1) (intermediate 156)

A solution of intermediate 155 (residue) in TFA/DCM/TIS (909/12) (5 ml)was stirred for 7-8 hours, then the solvent was evaporated and theobtained residue was dried overnight in an oven, yielding intermediate156, isolated as a trifluoro acetic acid salt.

EXAMPLE A33 a) Preparation of (S)proline,1-[(4-chloro-5-fluoro-2-nitrophenyl)methyl]-, 1,1-dimethylethyl ester(intermediate 157)

A solution of L-Proline, 1,1-dimethylethyl ester (0.010 mol) and4-chloro-5-fluoro-2-nitro-benzaldehyde (0.010 mol) in DCM (30 ml) wascooled to 0° C. and tetrakis (2-propanolato) titanium (0.010 mol) wasadded., then the mixture was stirred for 1 hour at RT and NaBH(OAc)₃(0.011 mol) was added. The reaction mixture was stirred for 3-hours atRT and extra tetrakis (2-propanolato) titanium (0.001 mol) andNaBH(OAc)₃ (0.001 mol) were added. The resulting mixture was stirred for6 hours at RT. Water was added and the mixture was filtered. The organiclayer was separated, dried, filtered off and the solvent was evaporated,yielding intermediate 157 (used as such in the next reaction step).

b) Preparation of (S) proline,1-[(2-amino-4-chloro-5-fluorophenyl)methyl]-, 1,1-dimethylethyl ester(intermediate 158)

A mixture of intermediate 157 (0.009 mol) in EtOAc (150 ml) washydrogenated with Pt/C 5% (1 g) as a catalyst in the presence ofthiophene solution (1 ml: 4% in DIPE). After uptake of H₂ (3 equiv.),the catalyst was filtered off and the filtrate was evaporated. Theresidue was purified by RP high-performance liquid chromatography, thenthe product fractions were collected and the organic solvent wasevaporated. The obtained precipitate was filtered off washed with waterand dried to give 1.1286 g (34%) of intermediate 158.

c) Preparation of (S)proline,1-[[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chloro-5-fluorophenyl]methyl]-,1,1-dimethylethyl ester

Intermediate 85 (0.001 mol) was added to a solution of intermediate 158(0.001 mol) in 2-propanol (q.s.) and then the reaction mixture wasstirred for 2 hours and the solvent was evaporated, yieldingintermediate 159 (used as such in the next reaction step).

d) Preparation of (S)proline,1-[[4-chloro-5-fluoro-2[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]methyl]-,1,1-dimethylethyl ester (intermediate 160)

NH₃/CH₃OH (10 ml) was added to intermediate 159 (0.001 mol) and thereaction mixture was shaken for 1 hour and then the solvent wasevaporated, yielding intermediate 160 (used as such in the next reactionstep).

e) Preparation of (S) proline,1-[[4-chloro-2-[[6-[3-[[(1,1-dimethylethoxy)carbonyl]amino]propoxy]-7-methoxy-4-quinazolinyl]amino]-5-fluorophenyl]methyl]-,1,1-dimethylethyl ester (intermediate 161)

A mixture of intermediate 160 (0.0005 mol), (3-bromopropyl)- carbamicacid, 1,1-dimethylethyl ester (0.12326 ml) and cesium carbonate (0.815g) was stirred overnight at RT and then the reaction mixture was stirredfor 30 min. at 50° C. Extra (3-bromopropyl)- carbamic acid,1,1-dimethylethyl ester (0.013 g) was added and the mixture was stirredfor 4 hours at RT and for another 15 min. at 50° C. The solvent wasevaporated and the residue was dissolved in DCM. This solution wasfiltered over dicalite and the filtrate was evaporated, yieldingintermediate 161.

f) Preparation of (S)proline,1-[[2-[[6-(3-aminopropoxy)-7-methoxy-4-quinazolinyl]amino]-4-chloro-5-fluorophenyl]methyl]-TFAsalt (intermediate 162)

A solution of intermediate 161 (residue) in TFA/DCM/TIS (90/8/2) (25 ml)was stirred overnight, then the solvent was evaporated and the obtainedresidue was dried overnight in an oven at 80° C., yielding intermediate162, isolated as trifluoroacetic acid salt.

EXAMPLE A34 a) Preparation of 5-hexenamide,N-[(2-amino-4-chlorophenyl)methyl]- (intermediate

A mixture of 5-hexenoic acid (0.0075 mol) and PL-DCC resin (0.015 mol;Polymer Laboratories: 3417) in DCM (100 ml) was stirred for 15 min. atRT, then 2-amino-4-chloro-benzenemethanamine (0.01125 mol) was added andthe resulting mixture was stirred for 3 hours. After addition ofmethylisocyanate polystyrene (0.01125 mol; Novabiochem: 01-64-0169), thereaction mixture was stirred for 4 hours, filtered and then the solventwas evaporated, yielding 1.43 g (76%) of intermediate 163.

b) Preparation of 5-hexenamide,N-[[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]methyl]-(intermediate 164)

A solution of intermediate 163 (0.0057 mol) and intermediate 85 (0.0052mol) in 2-propanol (20 ml) was stirred for 5 hours at 60° C. and thenthe mixture was cooled. 7N NH₃ in methanol (20 ml) was added and thereaction mixture was stirred for 2 hours at RT. Finally, the solvent wasevaporated, yielding 1.5 g of intermediate 164.

c) Preparation of 5-hexenamide,N-[[4-chloro-2-[[7-methoxy-6-(4-pentenyloxy)-4-quinazolinyl]amino]phenyl]methyl]-(intermediate 165)

A mixture of intermediate 164 (0.0018 mol) and cesium carbonate (0.0090mol) in DMF (20 ml) was stirred for 15 min., then 5-bromo-1-pentene(0.0021 mol) was added and the reaction mixture was stirred overnight atRT. Water and DCM were added and the layers were separated. The organiclayer was washed with a 10% citric acid solution and with brine, then itwas dried (MgSO₄), filtered and the solvent was evaporated. The residue(0.694 g) was then purified by RP high-performance liquidchromatography. The product fractions were collected and the solvent wasevaporated, yielding 0.270 g of intermediate 165.

EXAMPLE A35 a) Preparation of (S)carbamic acid,[1-[[[(4-chloro-2-nitrophenyl)methyl]amino]carbonyl]-3-butenyl]-,1,1-dimethylethyl ester (intermediate 166)

1-[bis(dimethylamino)methylene]-1H-benzotriazolium, hexafluorophosphate(1-), 3-oxide (0.0056 mol) was slowly added to a solution of2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-pentenoic acid (0.0046 mol),4-chloro-2-nitro-benzenemethanamine (0.0056 mol),1-hydroxy-1H-benzotriazole (0.0056 mol) and DIPEA (0.93 ml) in DMF (25ml) and then the reaction mixture was stirred for 3 hours at RT. Themixture was diluted with EtOAc (200 ml) and then washed with a 10% aq.citric acid solution (50 ml), with water (50 ml), with an aqueous NaHCO₃solution (50 ml) and with brine (50 ml). The organic layer wasseparated, dried (MgSO₄), filtered off and the solvent was evaporated,yielding 2.00 g (100%) of intermediate 166.

b) Preparation of (S)carbamic acid,[1-[[[(2-amino-4-chlorophenyl)methyl]amino]carbonyl]-3-butenyl]-1,1-dimethylethylester (intermediate 167)

A mixture of intermediate 166 (0.003 mol) and tin(II) chloride dihydrate(0.015 mol) in ethanol (50 ml) was stirred for 90 min. at 60° C., thenthe reaction mixture was poured out into water and extracted 3 timeswith toluene. The organic layer was separated, dried (MgSO₄), filteredoff and the solvent was evaporated (vacuum), yielding intermediate 167.

c) Preparation of (S) carbamic acid,[1-[[[[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]methyl]amino]carbonyl]-3-butenyl]-1,1-dimethylethylester (intermediate 168)

A solution of intermediate 167 (0.003 mol) and intermediate 85 (0.0025mol) in 2-propanol (150 ml) was stirred overnight at 55° C. and then themixture was cooled. 7N NH₃ in methanol (50 ml) was added and thereaction mixture was stirred for 2 hours at RT. Finally, the solvent wasevaporated, yielding 2.17 g of intermediate 168.

d) Preparation of (S)carbamic acid,[1-[[[[4-chloro-2-[[7-methoxy-6-(4-pentenyloxy)-4-quinazolinyl]amino]phenyl]methyl]amino]carbonyl]-3-butenyl]-,1,1-dimethylethyl ester (intermediate 169)

A solution of intermediate 168 (0.0015 mol) and cesium carbonate (0.0075mol) in DMF (30 ml) was stirred for 15 min. at RT, then5-bromo-1-pentene (0.0018 mol) was added and the reaction mixture wasstirred for 24 hours at RT. Water and DCM were added and the layers wereseparated. The organic layer was washed with a 10% citric acid solutionand with brine, then it was dried (MgSO₄), filtered and the solvent wasevaporated, yielding intermediate 169.

EXAMPLE A36 a) Preparation of 1-pentanol,5-[2-(2-amino-4-chlorophenyl)ethoxy]-, acetate (ester) (intermediate170)

Reaction (I): A mixture of 2,6-bis(1,1-dimethylethyl)- pyridine (0.012mol) and 4-chloro-2-nitro- benzeneethanol (0.01 mol) in1,2-dichloro-ethane (30 ml) was stirred under N₂ and at 0° C., then amixture of triflic anhydride (0.011 mol) in 1,2-dichloro-ethane (10 ml)was added dropwise at 0° C. and the reaction mixture was stirred for 1hour at RT, to give Mixture. (I). Reaction (II): A solution of1,5-pentanediol, monoacetate (0.011 mol) in 1,2-dichloro-ethane (10 ml)was added dropwise to Mixture (I) and the resulting mixture was stirredfor 1 hour at 65° C. After cooling, water was added and the mixture waspartitioned between ethanol/DCM. The organic layer was separated, driedfiltered off and the solvent was evaporated. The obtained residue waspurified by flash column chromatography (eluent: DCM/CH₃OH 100/0, 98/2).The product fractions were collected and the solvent was evaporated, togive Mixture (II). A mixture of Mixture (II) (0.0133 mol) in THF (50 ml)was hydrogenated 2 times at 50° C. with Pt/C (1 g) as a catalyst in thepresence of thiophene solutions (1 ml). After uptake of H₂ (3 equiv.),the catalyst was filtered off and the filtrate was evaporated. Theobtained residue was purified over silica gel on a glass filter (eluent:Hexane/EtOAc 80/20, 70/30). The product fractions were collected and thesolvent was evaporated, yielding 1.5 g of intermediate 170.

b) Preparation of 6-quinazolinol,4-[[2-[2-[[5-(acetyloxy)pentyl]oxy]ethyl]-5-chlorophenyl]amino]-7-methoxy-,acetate (ester) (intermediate 171)

A mixture of intermediate 170 (0.005 mol) and intermediate 85 (0.005mol) in dioxane (20 ml) was reacted for 16 hours at 80° C. and then thesolvent was evaporated, yielding intermediate 171.

c) Preparation of 6-quinazolinol,4-[[5-chloro-2-[2-[(5-hydroxypentyl)oxy]ethyl]phenyl]amino]-7-methoxy-(intermediate 172)

A mixture of intermediate 171 (residue) and potassium carbonate (5 g) inwater (50 ml) and methanol (50 ml) was stirred overnight at RT, thenwater was added and the mixture was extracted with DCM. The organiclayer was washed 2 times with water, then dried, filtered and thesolvent was evaporated. Toluene was added and the solvent was evaporatedagain, yielding 2 g of intermediate 172.

EXAMPLE A37 a) Preparation of carbamic acid,[3-(4-chloro-2-nitrophenyl)-2-propynyl]-, 1,1-dimethylethyl ester(intermediate 173)

A mixture of 1-bromo-4-chloro-2-nitro- benzene (0.15 mol),dichlorobis(triphenylphosphine)-palladium (0.0075 mol) and copper (I)iodide (0.0075 mol) in triethylamine (300 ml) was stirred at 50° C. and2-propynyl- carbamic acid, 1,1-dimethylethyl ester (0.375 mol) was addedportionwise, then the reaction mixture was stirred for 2 hours at 50° C.and the solvent was evaporated. The residue was taken up in water andthe mixture was extracted with EtOAc. The organic layer was separated,dried, filtered off and the solvent was evaporated. The residue waspurified twice by column chromatography (eluent: Hexane/EtOAc 80/20).The product fractions were collected and the solvent was evaporated. Theobtained residue (31.8 g) was stirred in hexane, and then the resultingprecipitate was filtered off and dried, yielding 31.5 g, (67.6%) ofintermediate 173.

b) Preparation of carbamic acid, [3-(2-amino-4-chlorophenyl)propyl]-,1,1-dimethylethyl ester (intermediate 174)

A mixture of intermediate 173 (0.04 mol) in THF (200 ml) washydrogenated at 50° C. for with Pt/C (3 g) as a catalyst in the presenceof thiophene solution (1 ml) (in the meantime; the catalyst was changed2 times). After uptake of H₂ (6 equiv.), the catalyst was filtered offand the filtrate was evaporated, yielding (66%) of intermediate 174.

c) Preparation of carbamic acid,[3-[2-[[6-(acetyloxy)-7-methoxy-4-quinazolinyl]amino]-4-chlorophenyl]propyl]-,1,1-dimethylethyl ester (intermediate 175)

A mixture of intermediate 174 (0.04 mol) and intermediate 85 (0.035 mol)in acetonitrile (100 ml) was; reacted for 3 hours at 75° C. and then thereaction mixture was cooled. The resulting precipitate was filtered offand dried, yielding 12.2 g (69.6%) of intermediate 175.

d) Preparation of butanoic acid, 4-[[4-[[5chloro-2-[3-[[(1,1-dimethylethoxy)carbonyl]amino]propyl]phenyl]amino]-7-methoxy-6-quinazolinyl]oxy]-,ethyl ester (intermediate 176)

A mixture of intermediate 175 (0.0020 mol) and potassium carbonate(0.00072 mol) in water (1 ml) and methanol (1 ml) was stirred for 16hours at RT and then the solvent was evaporated. The residue was takenup in water, then the mixture was neutralised with NaOAc and extractedwith DCM. The organic layer was separated, dried, filtered off and thesolvent was evaporated, yielding 0.850 g of intermediate 176.

(e) Preparation of butanoic acid,4-[[4-[[2-(3-aminopropyl)-5-chlorophenyl]amino]-7-methoxy-6-quinazolinyl]oxy]-(intermediate 177)

A mixture of intermediate 176 (0.00035 mol) in THF (10 ml)/HCl 36% (2ml)/water (3 ml) was reacted for 16 hours at RT and then the solvent wasevaporated. The obtained residue was stirred in acetonitrile, then theresulting precipitate was filtered off and dried, yielding 0.200 g ofintermediate 177.

EXAMPLE A38 a) Preparation of carbamic acid,[3-[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]propyl]-,1,1-dimethylethyl ester (intermediate 178)

A mixture of hydrochloric acid salt of intermediate 175 (0.056 mol) andpotassium carbonate (25 g) in water (250 ml) and methanol (200 ml) wasstirred for 6 hours at RT and then the solvent was evaporated. Theresidue was taken up in a small amount of water, then NaOAc (25 g) wasadded and the mixture was extracted with DCM/CH₃OH. The organic layerwas separated, dried, filtered off and the solvent was evaporated. Theobtained residue was stirred in DIPE and after filtration the filterresidue was dried, yielding 23.5 g (91.5%) of intermediate 178.

b) Preparation of 6-quinazolinol,4-[[2-(3-aminopropyl)-5-chlorophenyl]amino]-7-methoxy-HCl (1:1)(intermediate 179)

A mixture of intermediate 178 (0.015 mol) in methanol (50 ml) andHCl/2-propanol (10 ml) was stirred for 16 hours at RT and then thesolvent was evaporated. The obtained residue was stirred in DIPE andafter filtration the filter residue was dried, yielding 6.1 g (94.6%) ofintermediate 179, isolated as a hydrochloric acid salt.

c) Preparation of acetamide,N-[3-[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]propyl]-2-[(2-hydroxyethyl)amino]-(intermediate 180)

Intermediate 179 (0.02 mol), DMF (100 ml) and DIPEA (0.1 mol) werestirred at 0-10° C., then a mixture of bromo- acetyl chloride (0.05 mol)in DCM (10 ml) was added dropwise and the reaction mixture was stirredfor 2 hours at RT, to give mixture (I). A mixture of 2-amino- ethanol(0.2 mol) in DMF (20 ml) was added dropwise to mixture (I) and theresulting mixture was stirred for 5 hours at 60° C. The solvent wasevaporated and the obtained residue was purified by RP high-performanceliquid-chromatography. The product fractions were collected and thesolvent was evaporated, yielding 10.7 g of intermediate 180.

d) Preparation of carbamic acid;[2-[[3-[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]propyl]amino]-2-oxoethyl](2-hydroxyethyl)-,1,1-dimethylethyl ester (intermediate 181)

A mixture of intermediate 180 (0.0043 mod) in DCM (50 ml) and THF (50ml) was stirred and dicarbonic acid, bis(1,1-dimethylethyl)ester (0.0046mol) was added, then the reaction mixture was stirred for 2 hours andthe solvent was evaporated. The residue was taken up in a small amountof water and the mixture was extracted with DCM. The organic layer wasseparated and the solvent was evaporated. The obtained residue was takenup in methanol and then CH₃OH/NH₃ was added. The mixture was stirred for2 hours and the solvent was evaporated. The residue was purified on aglass filter (eluent: DCM/CH₃OH 90/10). The product fractions werecollected and the solvent was evaporated, yielding 0.500 g ofintermediate 181.

EXAMPLE A39 Preparation of

A mixture of intermediate 179 (0.016 mol) in DMF (80 ml) was stirred andDIPEA (0.040 mol) was added to give Solution (*)2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene (0.00528 mol,Novabiochem: 01-64-0269 previously washed with DCM, was stirred in DCM120 ml), then tetrakis (2-propanolato) titanium 0.016 mol) was added andthe mixture was stirred. Solution (*) was added and the resultingmixture was stirred for 2 hours. After addition of NaBH(OAc)₃ (0.016mol), the reaction mixture was stirred for 16 hours and was filteredoff. The filter residue was washed 2 times with DCM (100 ml)/THF (100ml), 3 times with successively DCM (200 ml) and methanol (200 ml) andfinally 3 times with DCM (200 ml). The washed residue was dried for 16hours at 50° C. and the desired product was collected, yielding 9.46 g(77%) of intermediate 182.

EXAMPLE A40 a) Preparation of 1,3-dioxolane-2-methanamine,N-[(2-amino-4-chlorophenyl)methyl]-N-methyl- (intermediate 183)

A solution of N-methyl-1,3-dioxolane-2-methanamine (0.020 mol) and4-chloro-2-nitro- benzaldehyde (0.010 mol) in methanol (200 ml) washydrogenated at 50° C. over the weekend with Pt/C (cat. quant., slurryin EtOAc) as a catalyst in the presence of thiophene solution (q.s., 4%in THF). After uptake of H₂ (4 equiv.), the reaction mixture wasfiltered over dicalite and the solvent was evaporated. The residue waspurified by RP high-performance liquid chromatography. The productfractions were collected and the organic component of the eluent wasevaporated. The precipetate was filtered off, to give 0.7879 g (31%) ofintermediate 183.

b) Preparation of 6-quinazolinol,4-[[5-chloro-2-[[(1,3-dioxolan-2-ylmethyl)methylamino]methyl]phenyl]amino]-7-methoxy-,acetate (ester) (intermediate 184)

A solution of intermediate 85 (0.00156 mol) and intermediate 183(0.00156 mol) in acetonitrile (15 ml) was stirred for 3 hours at 80° C.and then the reaction mixture was allowed to cool overnight. The mixturewas stirred for another hour at 80° C. and then 3 drops of glacialacetic acid was added. The resulting mixture was stirred at 80° C. andagain glacial, acetic acid (1 ml) were added. After stirring overnightat 80° C., the mixture was cooled to RT and the obtained precipitate wasfiltered off. The filtrate was evaporated and the residue was dried inan oven, yielding intermediate 184 (used as such in the next reactionstep).

c) Preparation of 6-quinazolinol,4-[[5-chloro-/—[[(1,3-dioxolan-2-ylmethyl)methylamino]methyl]phenyl]amino]-7-methoxy-(intermediate 185)

A solution of intermediate 184 (0.00156-mol) in NH₃/H₃OH (q.s.) wasstirred for 1 hour at RT and then the reaction mixture was filtered, togive filter residue and filtrate. The filtrate was triturated withacetonitrile and then the desired product was collected, yielding 0.1350g of intermediate 185.

d) Preparation of carbamic acid,[3-[[4-[[5-chloro-2-[[(1,3-dioxolan-2-ylmethyl)methylamino]methyl]phenyl]amino]-7-methoxy-6-quinazolinyl]oxy]propyl]-,1,1-dimethylethyl ester (intermediate 186)

cesium carbonate (0.00464 mol) was added to a solution of intermediate185 (0.00093 mol) in DMF (9 ml) and the mixture was stirred for 1 hourat RT. (3-bromopropyl)-carbamic acid, 1,1-dimethylethyl ester (0.00093mol) was added and the reaction mixture was stirred overnight at RT,then the solvent was evaporated and the residue was dissolved in DCM.This solution was filtered over dicalite and the filtrate was evaporatedto dryness, yielding intermediate 186(used as such in the next reaction

EXAMPLE A41 a) Preparation of benzenemethanamine,4-chloro-N-methyl-2-nitro-N-2-propenyl-(intermediate 187)-

A solution of 4-chloro-2-nitro- benzaldehyde (0.010 mol) andN-methyl-2-propen-1-amine (0.010 mol) in DCM (q.s.) was stirred for 15hours at RT, then NaBH(OAc)₃ (0.011 mol) was added and the reactionmixture was stirred for 3.5 hours at RT. Extra NaBH(OAc)₃ (0.002 mol)was added and the mixture was filtered over silica gel (eluent: DCM).The second fraction was repurified by column chromatography over silicagel and combined with previously obtained 1st fraction and then thesolvent was evaporated, yielding 2.0689 g (86%) of intermediate 187.

b) Preparation of benzenemethanamine,2-amino-4-chloro-N-methyl-N-2-propenyl-(intermediate 188)

Tin (II) chloride dihydrate (0.043 mol) was added to a solution ofintermediate 187 (0.0086 mol) in ethanol (40 ml) and after stirring thereaction mixture was heated for 90 min. at 50° C. A saturated aqueousNaHCO₃ solution was added, followed by addition of DCM, then the layerswere separated and the separated organic layer was filtered. The aqueouslayer was extracted 3 times with DCM and the separated organic layer wasfiltered again. The filter residue was washed 3 times with DCM and theorganic layer of the filtrate was separated, then dried, filtered andthe solvent was evaporated, yielding 1.3772 g (76%) of intermediate 188.

c) Preparation of 6-quinazolinol,4-[[5-chloro-2-[(methyl-2-propenylamino)methyl]phenyl]amino]-7-methoxy-,acetate (ester) (intermediate 189)

Intermediate 85 (0.016 mol) was added to a solution of intermediate 188(0.0016 mol) in 2-propanol (20 ml), then reaction mixture was stirredfor 3 hours at 80° C. and the desired product was collected, yieldingintermediate 189.

d) Preparation of 6-quinazolinol,4-[[5-chloro-2-[(methyl-2-propenylamino)methyl]phenyl]amino]-7-ethoxy(intermediate 190)

A solution of intermediate 189 (0.0016 mol) in NH₃/CH³OH (10 ml) wasshaken for 1 hour and then the solvent was evaporated to dryness,yielding intermediate 190.

e) Preparation of 4-quinazolinamine,6-(3-butenyloxy)-N-[5-chloro-2-[(methyl-2-propenylamino)methyl]phenyl]-7-methoxy-(intermediate 191)

A mixture of intermediate 190 (0.00042 mol), 4-bromo-1-butene (0.0005mol) and cesium carbonate (q.s.) in DMF (q.s.) was stirred overnight atRT and then the solvent was evaporated. The dry residue war dissolved inDCM and the obtained solution was filtered over dicalite, then thedesired product was collected, yielding intermediate 191.

EXAMPLE A42 a) Preparation of 1H-isoindole-1,3(2H)-dione,2-[2-(4-chloro-2-nitrophenyl)ethyl](intermediate 192)

A mixture of 4-chloro-1-(2-chloroethyl)-2-nitro- benzene (0.37 mol) and1H-isoindole-1,3(2H)-dione, potassium salt (0.55 mol) in DMF (1000 ml)was reacted for 2 hours at 90° C., then the reaction mixture was cooledand poured out into ice-water. The resulting mixture was stirred for 30min. at RT and the precipitate was filtered off. The filter residue wasdissolved in DCM with MgSO₄ and after filtration the filtrate wasevaporated. Yield: 118 g (96%) of intermediate 192.

b) Preparation of benzeneethanamine, 4-chloro-2-nitro- (intermediate193)

Hydrazine, monohydrate (2.0 mol) was slowly added dropwise to a mixtureof intermediate 192 (0.37 mol) in methanol (1000 ml) and then thereaction mixture was reacted for 6 hours at 55° C. After filtration, thefiltrate was evaporated and water was added to the obtained residue. Themixture was extracted 3 times with toluene, then the organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated,yielding 61.5 g of intermediate 193.

c) Preparation of benzeneethanamine, 2-amino-4-chloro-(intermediate 194)

A mixture of intermediate 193 (0.225 mol) in THF (500 ml) washydrogenated with, Pt/C 5% (5 g) as a catalyst in the presence ofthiophene solution (5 ml). After uptake of H₂ (3 equiv.), the catalystwas filtered off and the filtrate was evaporated. The obtained residuewas dissolved in toluene and a 1N HCl solution (600 ml), then thissolution was stirred for 1 hour at 60° C. and after cooling sodiumhydroxide was added until pH: 9. The organic layer was separated and theaqueous layer was extracted 2 times with toluene. The organic layerswere combined, dried: (MgSO₄), filtered off and the solvent wasevaporated, yielding 30 g of intermediate 194.

d) Preparation of (S) carbamic acid,[2-[[2-(2-amino-4-chlorophenyl)ethyl]amino]-1-methyl-2-oxoethyl]-1,1-dimethylethylester (intermediate 195)

A mixture of N-[(1,1-dimethylethoxy)carbonyl]-L-Alanine (0.0015 mol) andPL-DCC resin (0.0030 mol; Polymer Laboratories, Part No 3417) in DCM (20ml) was stirred for 30 min at RT. A mixture of1-[bis(dimethylamino)methylene]-1H-benzotriazolium, hexafluorophosphate(1-), 3-oxide (0.0015 mol) in a small amount of DMF (5 ml) was added. Amixture of intermediate 194 (0.00225 mol) in DCM (2 ml) was added andthe reaction mixture was stirred for 5 hours, then methylisocyanatepolystyrene (0.00225 mol; NovaBiochem, No 01-640169) was added [andadditionally, (polystyrylmethyl)trimethylammonium bicarbonate (0.00450mol; NovaBiochem, No 01-64-0419) was added. After 15 hours, the reactionmixture was filtered and the solvent was evaporated, yieldingintermediate 195.

e) Preparation of (S) carbamic acid,[2-[[2-[4-chloro-2-[(6-hydroxy-7-methoxy-4-quinazolinyl)amino]phenyl]ethyl]amino]-1-methyl-2-oxoethyl]-1,1-dimethylethylester (intermediate 196)

A solution of intermediate 195 (0.00110 mol) and intermediate 85(0.00100 mol) in 2-propanol (20 ml) was stirred for 5 hours at 50° C.,then the mixture was cooled and NH₃, 7N in methanol (10 ml) was added.The reaction mixture was stirred for 2 hours at RT and the solvent wasevaporated, yielding intermediate 196.

f) Preparation of (S) acetic acid,[[4-[[2-[2-[(2-amino-1-oxopropyl)amino]ethyl]-5-chlorophenyl]amino]-7-methoxy-6-quinazolinyl]oxy]-.HCl(1:1) (intermediate 197)

Step I ‘alkylation with chloroacetate’: A solution of intermediate 196(0.001 mol), chloro- acetic acid, methyl ester (0.002 mol) and potassiumcarbonate (0.003 ml) in acetonitrile dry (20 ml) was stirred for 3 hoursat 75° C., then water (2 ml) and DCM (10 ml) were added and the reactionmixture was stirred for 5 min. at RT. The mixture was filtered throughIsolute HM-N cartridges, followed by elution with DCM and then thesolvent was evaporated, to give Residue (1). Step II ‘deprotection’: Asolution of Residue (I) in concentrated HCl (2.5 ml), water (2.5 ml) anddioxane (5.0 ml) was stirred for 24 hours at 60° C. and then the solventwas evaporated, yielding intermediate 197 isolated as a hydrochloricacid salt (1:1).

EXAMPLE A43 a) Preparation of carbamic acid,[4-[[(4-chloro-2-nitrophenyl)methyl]amino]oxobutyl]-, 1,1-dimethylethylester (intermediate 198)

N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine (0.0049 mol) wasadded portionwise to a mixture of4-[[(1,1-dimethylethoxy)carbonyl]amino]- butanoic acid (0.0049 mol),4-chloro-2-nitro-benzenemethanamine (0.0041 mol) and DIPEA (0.0049 mol)in DMF (30 ml) at and then the reaction mixture was stirred 3 hours atRT. The mixture was diluted with EtOAc (150 ml), washed with a 10%aqueous citric acid solution, with water, with an aqueous NaHCO₃solution and then with brine. The organic layer was separated, dried,filtered off and the solvent was evaporated, yielding 1.225 g ofintermediate 198.

b) Preparation of carbamic acid,[4-[[(2-amino-4-chlorophenyl)methyl]amino]-4-oxobutyl]-,1,1-dimethylethyl ester (intermediate 199)

A mixture of intermediate 198 (0.003 mol) in THF (25 ml) and methanol(25 ml) was hydrogenated at 50° C. with Pt/C 5% (0.5 g) as a catalyst inthe presence of thiophene solution (0.5 ml). After uptake of H₂ (3equiv.), the catalyst was filtered off and the filtrate was evaporated,yielding intermediate 199.

c) Preparation of carbamic acid,[4-[[[4-chloro-27[(6-hydroxy-7-methoxy-4-quinazolinyl-amino]phenyl]methyl]amino-4-oxobutyl]-,1,1-dimethylethyl ester (intermediate 120)

A solution of intermediate 199 (0.0033 mol) and intermediate 85 (0.00275mol) in 2-propanol (100 ml) was stirred for 3 hours at 50° C. and aftercooling NH₃, 7N in to methanol (50 ml) was added. The reaction mixturewas stirred for 2 hours and then the solvent was evaporated, yieldingintermediate 120.

d) Preparation of acetic acid,[[4-[[5-chloro-2-[[[4[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxobutyl]amino]methyl]phenyl]amino]-7-methoxy-6-quinazolinyl]oxy]-,methyl ester (intermediate 121)

A mixture of intermediate 120 (0.001 mol), potassium carbonate (0.003mol) and chloro- acetic acid, methyl ester (0.003 mol) in acetonitrile(10 ml) was stirred for 3 hours at 75° C., then the reaction mixture wasfiltered over silica gel and the filter residue was washed with2-propanone. Finally, the filtrate was evaporated overnight undervacuum, yielding intermediate 121.

e) Preparation of acetic acid,[[4-[[2-[[(4-amino-1-oxobutyl)amino]methyl]-5-chlorophenyl]amino]-7-methoxy-6-quinazolinyl]oxy]-(intermediate 122)

A solution of intermediate 121 (0.001 mol) in HCl concentrated (3 ml),THF (6 ml) and water (3 ml) was stirred for 24 hours at 60° C. and thenthe solvent was evaporated, yielding intermediate 122.

B. Preparation of the Compounds

EXAMPLE B1 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaacyclo-pentadecin-8(9H)-one,10,11,12,13-tetrahydro-20-methoxy-15-methyl- (compound 1)

A solution of intermediate 5 (0.00008 mol),N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine (0.00024 mol)and DMC (5 ml) was stirred at RT and thenN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,monohydrochloride (0.00008 mol) was added. The reaction mixture wasstirred over the weekend at RT. The reaction was completed and themixture was washed 2 times with H₂O. The organic layer was separated,dried (MgSO₄), filtered off and the solvent was evaporated. The residuewas purified by high-performance liquid chromatography over RP-18(Normal Phase). The product fractions were collected, the solvent wasevaporated and the residue was dried (vac.) at 65° C., yielding 0.009 gof compound 1.

EXAMPLE B2 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine,15-chloro-8,9,10,11,12,13-hexahydro-20-methoxy- (compound 2)

A solution of intermediate 9 (0.0024 mol) and triphenylphosphine (0.0036mol) in THF, dry (100 ml) was stirred at RT and then a solution ofbis(1-methylethyl)diazenedicarboxylate (0.0036 mol) in THF (10 ml) wasadded dropwise. The reaction mixture was stirred for 6 hours and extrabis(1-methylethyl)diazenedicarboxylate (0.35 ml) in THF (10 ml) wasadded. The mixture was stirred overnight and concentrated. The residuewas purified by column chromatography over silica gel (eluent:DCM/CH₃OH/THF 90/5/5). The product fractions were collected and furtherpurified by RP high-performance liquid chromatography. The productfractions were collected and concentrated. The aqueous concentrate wasfiltered, and the solid retained washed and dried (vac.) at 65° C.,yielding 0.065 g of compound 2, melting point 255.5-260.2° C.

EXAMPLE B3 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benizodioxaazacyclo-pentadecine,17-chloro-8,9,10,11,12,13-hexahydro-20-methoxy- (compound 3)

A solution of intermediate, 13 (0.0012 mol) and tributylphosphine(0.0018 mol) in THF (dry)(50 ml) was stirred under N₂ conditions at RTand then a mixture of 1,1′-(azodicarbonyl)bis-piperidine (0.0018 mol) inTHF (dry) (10 ml) was added dropwise. The reaction mixture was stirredovernight and extra tributylphosphine (0.30 ml) was added. The mixturewas stirred for another 4 hours and the solvent was evaporated. Theresidue was purified by RP high-performance liquid chromatography andthe product fractions were collected and concentrated, the aqueousconcentrate was filtered, and the solid retained washed and dried (vac.)at 65° C., yielding 0.040 g of compound 3, melting point 241.5-242.7° C.

EXAMPLE B4 Preparation of4,6-ethanediylidene-8H,18H-pyrimido[4,5-b][6,12,1]benzo-dioxaazacyclotetradecine,16-chloro-9,10,11,12-tetrahydro-19-methoxy- (compound 4)

A solution of intermediate 17 (0.001 mol) and tributylphosphine (0.01 2mol) in (40 ml) was stirred at RT under N₂ and then a solution off1,1-(azodicarbonyl)bis-piperidine (0.0012 mol) in THF (10 ml) was addeddropwise. The reaction mixture was stirred for 4 h and then an extraamount of tributylphosphine (1 ml) and1,1′-(azodicarbonyl)bis-piperidine-(1 g) were added. The resultingmixture was stirred overnight and the solvent was concentrated underreduced pressure. The residue was purified by RP high-performance liquidchromatography. The product fractions were collected and the organicsolvent was evaporated. The resulting precipitate was filtered, washedand dried (vacuum) at 65° C., yielding 0.065 g of compound 4, meltingpoint 213.5-221.2° C.

EXAMPLE B5 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine,8,9,10,11,12,13-hexahydro-20-methoxy- (compound 5)

A solution of intermediate 21 (0.0013 mol) and tributylphosphine (0.002mol) in THF (50 ml) was stirred at RT and then a solution of1,1′-(azodicarbonyl)bis-piperidine (0.002 mol) in THE (5 ml) was added.After addition, the reaction mixture was stirred for 6 hours and thereaction was completed. The solvent was evaporated and the residue waspurified by RP high-performance liquid chromatography. The productfractions were collected and the organic solvent was evaporated. Theaqueous concentrate was filtered and the solid retained washed and dried(vac.) at 65° C., yielding 0.100 g of compound 5, melting point243.3-251.2° C.

EXAMPLE B6 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine,17-bromo-8,9,10,11,12,13-hexahydro-20-methoxy- (compound 6)

A solution of intermediate 25 (0.00079 mol) and tributylphoshine(0.00316 mol) in THF, dry (50 ml) was stirred at RT under N₂-atm., thena solution of 1,1′-(azodicarbonyl)bis-piperidine (0.00316 mol) in THF,dry (10 ml) was added and the reaction mixture was stirred for 12 hoursat RT under N₂-atm. The solvent was evaporated, the residue was stirredin DIPE and the mixture was filtered. The filtrate and the residue werecombined and purified by RP high-performance liquid chromatography. Theproduct fractions were collected and concentrated, yielding 0.180 g(51%) of compound 6, melting point 228.6-234.8° C.

EXAMPLE B7 Preparation of4,6-ethanediylidene-8H,20H-pyrimido[4,5-b][6,14,1]benzo-dioxaazacyclohexadecine,18-chloro-9,10,11,12,13,14-hexahydro-21-methoxy-(compound 7)

Tributylphoshine (0.0017 mol) and 1,1′-(azodicarbonyl)bis-piperidine(0.0017 mol) were added at RT to a solution of intermediate 29 (0.0012mol) in THF (80 ml) and reaction mixture was stirred for 2 hours. Thesolvent was evaporated under reduced pressure and the residue wasstirred in boiling DIPE/CH₃CN (20 ml/5 ml). This mixture was filtered,the solid retained was washed with CH₃CN and purified by RPhigh-performance liquid-chromatography. The product fractions werecollected and the organic solvent was evaporated. The aqueousconcentrate was filtered, and the solid retained washed and dried (vac.)at 65° C., yielding 0.145 g (30%) of compound 7, melting point240.6-243.7° C.

EXAMPLE B8 Preparation of4,6-ethanediylidene-21H-pyrimido[4,5-b][6,15,1]benzodioxaazacyclo-heptadecine,19-chloro-8,9,10,11,12,13,14,15-octahydro-22-methoxy- (compound 8)

A solution of intermediate 33 (0.0045 mol) in THF (200 ml) was stirredat RT and tributylphosphine (0.0047 mol), then1,1′-(azodicarbonyl)bis-piperidine (0.0047 mol) were added. The reactionmixture was stirred for 4 hours and the solvent was evaporated until 2/3of the initial volume. The mixture was filtered and the residue washedwith a small amount of THF. The filtrate was concentrated and thisresidue was suspended in H₂O and stirred. The resulting precipitate wascollected by filtration, washed with water and treated with boiling2-propanol. The mixture was cooled and filtered, the solid retained waswashed with 2-propanol and DIPE and dried (vac.) at 60° C., yielding 1.4g (74%) of compound 8, melting point 147.7-151.1° C.

EXAMPLE B9 Preparation of4,6-ethanediylidene-8H,22H-pyrimido[4,5-b][6,16,1]benzo-dioxaazacyclooctadecine,20-chloro-9,10,11,12,13,14,15,16-octahydro-23-methoxy-(compound 9)

A solution of intermediate 37 (0.0022 mol) in THF (100 ml) was stirredat RT and tributylphosphine (0.0023 mol), then1,1′-(azodicarbonyl)bis-piperidine (0.0023 mol) was added. The reactionmixture was stirred for 4 hours and the solvent was evaporated until 2/3of the initial volume. The precipitate was filtered and washed with asmall amount of THF. The filtrate was concentrated and the residue wasstirred in H₂O. The resulting precipitate was collected by filtration,washed with water and treated with boiling 2-propanol. The mixture wascooled and filtered, then the solid retained was washed with 2-propanoland with DIPE and dried (vacuum) at 60° C.), yielding 0.6 g (63%) ofcompound 9, melting point 177.4-183.8° C.

EXAMPLE B10 a) Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine-17-carboxylicacid, 8,9,10,11,12,13-hexahydro-20-methoxy-, methyl ester (compound 10)

A mixture of compound 6 (0.0005 mol), Pd(OAC)₂ (0.022 g),1,3-propanediylbis[diphenyl-phosphine] (0.088 g) and potassiumacetate(0.100 g) in methanol (q.s.; dry) was reacted under CO-gas (30 atm) for16 hours at 125° C. The solvent was evaporated. The residue was taken upinto water and this mixture was extracted with DCM. The separatedorganic layer was dried, filtered and the solvent evaporated. Theresidue was purified by HPLC over X-Terra (gradient elution with eluent:CH₃CN/CH₃OH/NH₄OAc). The product fractions were collected and thesolvent was evaporated. The residue was taken up into water, alkalisedwith K₂CO₃, then extracted with DCM. The separated organic layer wasdried, filtered and the solvent evaporated, yielding 0.057 g of compound10.

b) Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine-17-carboxylicacid, 8,9,10,11,12,13-hexahydro-20-methoxy- (compound

A mixture of compound 10 (0.0002 mol) in THF (3 ml), methanol (3 ml),NaOH 1N (1 ml) and H₂O (2 ml) was stirred at 50° C. for 3 hours. Thesolvent was evaporated. Water (2 ml) was added. HCl (1 N, 1 ml) wasadded and the mixture was stirred for a while. The precipitate wasfiltered off, washed with water, then filtered off again and stirred inTHF, then filtered off and dried, yielding 0.036 g of compound 11.

EXAMPLE B11 Preparation of pyrrolidine,1-[(8,9,10,11,12,13-hexahydro-20-methoxy-4,6-ethane--diylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecin-17-yl)carbonyl](compound12)

A mixture of compound 6(0.0004 mol), Pd(OAc)₂ (6-0.011 g),1,3-propanediylbis[diphenyl-phosphine] (0.044 g) and pyrrolidine (0.100g) in THF (q.s., dry) was reacted under CO-gas (30 atm) for 16 hours at125° C. The solvent was evaporated. The residue was taken up into waterand this mixture was extracted with DCM. The separated organic layer wasdried, filtered and the solvent evaporated. The residue was purified byHPLC over X-Terra (gradient elution with eluent: CH₃CN/CH₃OH NH₄OAc).The product fractions were collected and the solvent was evaporated. Theresidue was taken up into water, alkalised with K₂CO₃, then extractedwith DCM. The separated organic layer was dried, filtered and thesolvent evaporated, yielding 0.051 g of compound 12.

EXAMPLE B12 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine-17-carbonitrile,8,9,10,11,12,13-hexahydro-20-methoxy- (compound 13)

A mixture of compound 6 (0.0002 mol),tris[μ-[(1,2-η:4,5-η)-(1E,4E)-1,5-diphenyl-,1,4-pentadien-3-one]]di-palladium,(0.011 g), 1,1′-bis(diphenylphosphino)-ferrocene (0.013 g), Zn (0.005 g)and Zn(CN)₂ (0.045 g) in (2-oxo-1-pyrrolidinyl)- methyl (2 ml) wasreacted in the microwave for 30 min at 150° C. Water (4 ml) was addedand this mixture was extracted three times with ethyl acetate. Thecombined organic layers were washed with water (2×), dried, filtered andthe solvent was evaporated. The residue was purified by reversed-phaseHPLC over X-Terra (gradient elution with eluent: CH₃CN/CH₃OH/NH₄OAc).The product fractions were collected and the solvent was evaporated. Theresidue was taken up into water, then alkalised with K₂CO₃. This mixturewas extracted with DCM. The separated organic layer was dried, filteredand the solvent evaporated, yielding 0.063 g (81%) of compound 13.

EXAMPLE B13 Preparation of morpholine,4-[(8,9,10,11,12,13-hexahydro-20-methoxy-4,6-ethane-diylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclbpentadecin-17-yl)carbonyl]-(compound14)

A mixture of compound 6 (0.0002 mol), Pd(OAc)₂ (0.022 g),1,3-propanediylbis[diphenyl-phosphine] (0.088 g) and morpholine (0.200g) in THF (q.s., dry) was reacted under CO-gas (30 atm) for 24 hours at125° C. The solvent was evaporated. The residue was taken up into waterand this mixture was extracted with DCM. The separated organic layer wasdried, filtered and the solvent evaporated. The residue was purified byHPLC over X-Terra (gradient elution with eluent: CH₃CN/CH₃OH/NH₄OAc).The product fractions were collected and the solvent was evaporated. Theresidue was taken up into water, alkalised with K₂CO₃, then % extractedwith DCM. The separated organic layer was dried, filtered and thesolvent evaporated, yielding 0.005 g of compound 14.

EXAMPLE B14 a) Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine,17-bromo-8,9,10,11,12,13-hexahydro-20-(phenylmethoxy)- (compound 15)

A solution of intermediate 47 (0.0026 mol) in THF (140 ml) was stirredat RT, tributylphosphine (0.0035 mol) was added and then ADDP (0.0035mol). The reaction mixture was stirred for 6 hours and extra ADDP(0.0035 mol) and tributylphosphine (0.0035 mol) were added. Theresulting mixture was stirred for 12 hours. The formed precipitate wasremoved and the solvent was evaporated under reduced pressure. Theresidue was dissolved in THF (100 ml) with molecular sieves. Extra ADDP(0.0035 mol) and tributylphosphine (0.0035 mol) were added and themixture was stirred for 2 hours. The resulting precipitate was filteredoff and the solvent was evaporated under reduced pressure. The residuewas filtered over silica gel (eluent: DCM/CH₃OH 98/2) the productfractions were collected and the solvent was evaporated, yielding 0.600g of compound 15.

b) Preparation of4,6-ethanediylidene-9H-pyrimido[4,5-b][6,13,1,i]benzodioxaazacyclo-pentadecin-20-ol,17-bromo-8,9,10,11,12,13-hexahydro- (compound 16)

A solution of compound 15 (0.0006 mol) and (methylthio)- benzene (0.006mol) in trifluoroacetic acid (6 ml) was stirred for 3 days at RT andthen the solvent was evaporated. The residue was quenched with H₂O andthe aqueous layer was extracted with DCM. The precipitate between thetwo layers was filtered off, washed and dried (vacuum) at 60° C.,yielding compound 16.

EXAMPLE B15 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine,17-bromo-8,9,10,11,12,13-hexahydro-20-[3-(4-morpholinyl)propoxy]-aceticacid (compound 17)

A mixture of compound 16 (0.000065 mol) and K₂CO₃ (0.00013 mol) in DMA 2ml) was stirred at 60° C. for 30 min., then4-(3-chloro-propyl)-morpholine (0.000065 mol) was added and the reactionmixture was stirred for 1 day at 60° C. Extra4-(3-chloro-propyl)-morpholine (0.000065 mol) was added and the mixturewas stirred for 1 day. After the starting material was consumed, themixture was purified by RP high-performance liquid chromatography. Theproduct fractions were collected and the organic solvent was evaporated.The aqueous concentrate was extracted with DCM/CH₃OH (98/2) and theorganic layer was dried (MgSO₄), filtered, then the solvent wasevaporated, yielding 0.004 g of compound 17.

EXAMPLE B16 a) Preparation of4,6-ethanediylidene-191—pyrimido[4,5-b][6,13,1]benzodioxaazacyclo-pentadecine,17-bromo-8,9,10,11,12,13-hexahydro- (compound 18)

A solution of intermediate 49 (0.0012 mol) in THF (50 ml) was stirred atRT under N₂ and tributylphosphine (0.0017 mol) was added, then1,1′-(azodicarbonyl)bis-piperidine (0.0017 mol) was added and thereaction mixture was stirred for 1 hour. The solvent was evaporateduntil 1/3 of the initial volume and the formed precipitate was filteredoff, then washed. The filtrate was evaporated and the residue wasquenched with H₂O. The mixture was acidified with HCl (1N) and extractedwith DCM/CH₃OH (99/1). The organic layer was dried (MgSO₄), filtered andthe solvent was evaporated. The residue was purified by Flash columnchromatography (eluent: DCM/CH₃OH 99/1). The product fractions werecollected and the solvent was evaporated. The residue was stirred inboiling 2-propanol, then the resulting precipitate was filtered off,washed with 2-propanol and with DIPE and dried (vacuum) at 60° C.,yielding 0.111 g of compound 18.

EXAMPLE B17 a) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclo-pentadecine-13(8H)-carboxylicacid, 17-bromo-9,10,11,12,14,19-hexahydro-20-methoxy-, 1,1-dimethylethylester (compound 19)

A solution of intermediate 55 (0.0021 mol) in THF (dry) (120 ml) wasstirred at RT and tributylphosphine (0.0032 mol) was added, then1,1′-(azodicarbonyl)bis-piperidine, (0.0032 mol) was added and thereaction mixture was stirred for 3 hours. The solvent was evaporateduntil 1/3 of the initial volume. The resulting precipitate was filteredoff and washed. The filtrate was evaporated and used as such in the nextreaction step. A part of the residue (0.200 g) was purified by RPhigh-performance liquid chromatography. The product fractions werecollected and the organic solvent was evaporated. The aqueousconcentrate was extracted with. DCM and the organic layer was dried(MgSO₄), filtered off, then the solvent was evaporated, yielding 0.005 gof compound 19.

b) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclo-pentadecine,17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy- (compound 20)

A solution of compound 19 (0.00092 mol) in mono(trifluoroacetate) (20ml) was stirred for 1 hour at RT, then the solvent was evaporated underreduced pressure and co-evaporated with toluene. The residue was stirredin boiling 2-propanol, then the resulting precipitate was filtered off,washed and dried. The filtrate was evaporated and the residue waspurified by RP high-performance liquid chromatography. The productfractions were collected and the organic solvent was evaporated. Theaqueous concentrate was filtered off, washed and dried (vac.) at 70° C.,yielding 0.040 g (5%) of compound 20.

EXAMPLE B18 a) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1]benzoxaazacyclopentadecine,17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy- (compound 21)

A solution of intermediate 60 (0.0011 mol) in THF dry (50 ml) wasstirred at RT and tributylphosphine (0.0016 mol) was added, then1,1′-(azodicarbonyl)bis-piperidine (0.0016 mol) was added and thereaction mixture was stirred for 4 hours. The solvent was evaporateduntil 1/3 of the initial volume. The resulting precipitate was filteredoff and washed. The filtrate was evaporated and the residue was purifiedby RP high-performance liquid chromatography. The product fractions werecollected and the organic solvent was evaporated. The aqueousconcentrate was filtered off, washed with H₂O and dried (vac.) at 65°C., yielding 0.037 g (7.5%) of compound 21.

EXAMPLE B19 a) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclo-pentadecine,17-bromo-8,9,10,11,12,3,14,19-octahydro-20-methoxy-13-methyl (compound22)

A solution of intermediate 65 (0.0011 mol) in THF (50 ml) was stirred atRT and tributylphosphine (0.0016 mol) was added, then1,1′-(azodicarbonyl)bis-piperidine (0.0016 mol) was added and thereaction mixture was stirred for 2 hours. The solvent was evaporateduntil 1/3 of the initial volume. The resulting precipitate was filteredoff and washed. The filtrate was evaporated and the residue was purifiedby RP high-performance liquid chromatography. The product fractions werecollected and the organic solvent was evaporated. The aqueousconcentrate was extracted 2 times with DCM and the organic layer wasdried (MgSO₄), then filtered off. The solvent was evaporated and theresidue was dried (vac.) at 50° C., yielding 0.004 g (0.8%) of compound22.

EXAMPLE B20 Preparation of4,6-ethanediylidene-13H-pyrimido[4,5-b][6,11,1]benzodioxaazacyclo-pentadecine,17-chloro-8,9,10,11,14,19-hexahydro-20-methoxy- (compound 23)

A mixture of intermediate 70 (0.0007 mol) in THF (50 ml) was stirreduntil complete dissolution and tributylphosphine (0.0014 mol) was added,then the mixture was stirred and ADDP (0.0014 mol) was added. Thereaction mixture was stirred at RT and then extra ADDP (q.s.) andtributylphosphine (q.s.) were added. The resulting mixture was stirredat 60° C. for 10 hours and again extra ADDP (q.s.) and tributylphosphine(q.s.) were added. The mixture was stirred at 100° C. for 16 hours. Thesolvent was evaporated and the residue was purified by HPLC. The productfractions were collected and the solvent was evaporated, yielding 0.017g of compound 23.

EXAMPLE B21 Preparation of4,6-ethanediylidene-23H-pyrimido[4,5-b][6,15,1,16]benzo-dioxadiazacyclononadecine,21-chloro-8,9,10,11,12,13,14,15-octahydro-24-methoxy-(compound 24)

A solution of intermediate 75(0.000355 mol) and tributylphosphine(0.000356 mol) in THF (20 ml) and DMF p.a. dried on molecular sieves (5ml) was treated with ADDP (0.000353 mol) and the reaction mixture wasstirred at RT, then extra ADDP (q.s.) and tributylphosphine (q.s.) wereadded and the reaction mixture was stirred at RT. The solvent wasevaporated and the residue was purified by HPLC the product fractionswere collected and the solvent was evaporated, yielding 0.0274 g (17%)of compound 24, melting point 127.2-132.2° C.

EXAMPLE B22 Preparation of22H-4,6-ethanediylidene-21,17-methenopyrimido[5,4-d][1,12,6]dioxaazacycloeicosine,8,9,10,11,12,13,14,15-octahydro-24-methoxy-(compound 25)

A solution of intermediate 79 (0.0012 mol) in THF (75 ml) was stirred atRT and then ADDP (0.0018 mol) and tributylphosphine (0.0018 mol) wereadded. The reaction mixture was stirred for 3 hours and extra ADDP(0.0018 mol) and tributylphosphine (0.0018 mol) were added. Theresulting mixture was stirred for 2 hours and the solvent was evaporatedunder reduced pressure. The residue was stirred in 2-propanol andfiltered off, then the filtrate was evaporated and the residue waspurified by HPLC. The product fractions were collected and the solventwas evaporated, yielding 0.0027 g (72%) of compound 25.

EXAMPLE B23 a) Preparation of4,6-ethenopyrimido[4,5-b][6,1,10]benzoxadiazacyclopentadecin-12(13H)-one,17-chloro-8,9,10,11,14,19-hexahydro-20-(methoxy-(compound 26)

ADDP (0.00034 mol) was added to a solution of intermediate 84 (0.00023mol) and tributylphosphine (0.0042 mol) in THF (20 ml) and DMF (20 ml)at RT and the reaction mixture was stirred at RT for 1 hour. Extra ADDPand tributylphosphine were added at RT and then the resulting mixturewas stirred for 1 hour at RT. The solvent was evaporated off and againextra ADDP and tributylphosphine were added. The mixture was warmed to100° C. and stirred for 18 hours at 100° C., then the solvent wasevaporated under reduced pressure and the residue was purified by HPLC.The product fractions were collected and the solvent was evaporated,yielding 0.0094 g (10%) of compound 26.

b) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecin-14(19H)-one,17-chloro-8,9,10,11,12,13-hexahydro-20-methoxy- (compound 27)

Compound 27 is made in a similar way as compound 26.

EXAMPLE B24 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecine,17-bromo-8,9,10,11,12,13-hexahydro-20-(2-methoxyethoxy)- (compound 28)

A mixture of compound 16 (0.00023 mol), 1-bromo-2-methoxy-ethane (0.0046mol) and K₂CO₃ (0.00046 mol) in DMA (10 ml) was stirred for 18 hours at60° C. and then the reaction mixture was quenched with ice-water. Theprecipitate was filtered off, washed and stirred in boiling 2-propanol.The resulting precipitate was filtered off, washed and dried (vacuum) at53° C., yielding 0.030 g (74%) of compound 28.

EXAMPLE B25 a) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine-13(8H)-carboxylicacid, 17-chloro-16-fluoro-9,10,11,12,14,19-hexahydro-20-methoxy-,1,1-dimethylethyl ester (compound 29)

Tributylphosphine (0.00044 mol) was added to a solution of intermediate93 (0.00022 mol) and ADDP (0.00044 mol) in THE (30 ml) and then extraADDP (0.00044 mol) and tributylphosphine (0.00044 mol) were added. Thereaction mixture was stirred was stirred over the weekend and thesolvent was evaporated. CH₃OH (5 ml) was added and the resulting mixturewas stirred, then filtered and the filtrate evaporated. The residue waspurified by reversed phase HPLC. The product fractions were collectedand the solvent was evaporated, yielding 0.04 g (35.2%) of compound 29.

b) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine,17-chloro-16-fluoro-8,9,10,11,12,13,14,19-octahydro-20-methoxy-(compound 30)

A solution of compound 29 (0.000077 mot) in CH₃OH (5 ml) was treatedwith HCl/2-propanol (6N) (1 ml) and then the reaction mixture wasstirred overnight at RT. The solvent was evaporated and the residue wasdiluted with DCM/NaHCO₃. After stirring the mixture for 1 hour, theorganic layer was separated, dried (MgSO₄), filtered off and the solventwas evaporated, yielding 0.0089 g (27.7%) of compound 30, melting point265.9-261.3° C.

EXAMPLE B26 a) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,11]benzoxadiazacyclopentadecine-12(13H)-carboxylicacid, 17-chloro-8,9,10,11,14,19-hexahydro-20-methoxy-, 1,1-dimethylethylester (compound 31)

A solution of intermediate 99 (0.00025 mol), ADDP (0.000375 mol) andtributylphosphine (0.000375 mol) in THF (20 ml) was stirred for 4 hoursat RT and then the solvent was evaporated until 1/3 of the initialvolume. The resulting precipitate was filtered off and washed, then thefiltrate was evaporated and the residue was purified by reversed phaseHPLC. The product fractions were collected and the solvent wasevaporated, yielding 0.02 g of compound 31.

b) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,11]benzoxadiazacyclopentadecine,17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxy- (compound 32)

A solution of compound 31 (0.00004 mol) in TFA, (5 ml) was stirred for 4hours at RT and then the solvent was removed under N₂ at 40° C. Theresidue was purified by HPLC. The product fractions were collected andthe solvent evaporated, yielding 0.0037 g (69%) of compound 32.

EXAMPLE B27 Preparation of4,6-etheno-19H-pyrimido[5,4-k][11,8,5,13]benzodioxadiazacyclopentadecine,17-chloro-8,9,10,11,12,13-hexahydro-20-methoxy-10-[2-(4-morpholinyl)ethyl]-(compound 33)

ADDP (0.00068 mol) and tributylphosphine (0.00085 mol) were added to asolution of intermediate 105 (0.00047 mol) in THF (30 ml) at RT and thenthe reaction mixture was stirred for 2 hours at RT. The solvent wasevaporated under reduced pressure and the residue was purified by columnchromatography over silica gel (eluent: DCM/(CH₃OH/NH₃) 99/1 to 80/20).The pure fractions were collected and the solvent was evaporated underreduced pressure. The residue (0.032 g) was then purified by HPLC. Theproduct fractions were collected and the solvent was evaporated,yielding 0.0055 g of compound 33.

EXAMPLE B28 a) Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecine,8,9,10,11,12,13-hexahydro-20-methoxy-17-phenyl- (compound 34)

A mixture of intermediate 88 (0.0001 mol), iodo- benzene (0.0002 mol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (cat.quant.,5%), sodium, carbonate 2M in water (0.0003 mol) in DMSO (2 ml) wasstirred at 80° C. for 3 hours, then the reaction mixture was poured outinto ice-water and the aqueous layer was extracted with DCM. The organiclayer was separated, dried, filtered off and the solvent was evaporatedunder reduced pressure. The residue was purified by columnchromatography over silica gel (eluent: DCM/CH₃OH 98/2). The productfractions were collected and the solvent was evaporated, yielding 0.016g (36%) of compound 34.

b) Preparation of benzonitrile,3-(8,9,10,11,12,13-hexahydro-20-methoxy-4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecin-17-yl)-(compound35)

Compound 35 is made on the same way accordingly compound 34.

EXAMPLE B29 Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,13]benzoxadiazacyclohexadecin-15(20H)-one,18-chloro-9,10,11,12,13,14 hexahydro-21-methoxy- (compound 36)

ADDP (0.0016 mol) was added to a mixture of intermediate 110 (0.0011mol) and tributylphosphine (0.0020 mol) in THF. (50 ml) and the reactionmixture was stirred for 1 hour at RT. The solvent was evaporated underreduced pressure, then the residue was stirred and refluxed in methanol(80 ml) for 1 hour. The resulting precipitate was filtered off anddissolved in DMF (50 ml). The solution was concentrated again underreduced pressure and the residue was stirred in methanol. Finally, theresulting precipitate was filtered off and dried, yielding 0.242 g (52%)of compound 36.

EXAMPLE B30 Preparation of4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecine,16-chloro-8,9,10,11,12,13-hexahydro-20-20-methoxy (compound 37)

A solution of intermediate 87 (0.00007 mol) in THF (3 ml) was stirred atRT and then ADDP (0.0001 mol) and tributylphosphine (0.0001 mol) wereadded. The reaction mixture was stirred for 18 hours and extra ADDP(0.0001 mol) and tributylphosphine (0.0001 mol) were added. Theresulting mixture was stirred for 18 hours and the solvent wasevaporated. The residue was purified by HPLC and the product- fractionswere collected, then the solvent was evaporated and the residue wasdried (vacuum) at 50° C., yielding 0.002 g of compound 37.

EXAMPLE B31 Preparation of4,6-ethanediylidene-8H,14H-pyrimido[4,5-b][6,12,1]benzodioxaazacyclohexadecine,18-chloro-9,10,11,12,15,20-hexahydro-21-methoxy- (compound 38)

A mixture of intermediate 172 (0.0046 mol) in THF (400 ml) was stirredat RT, then tributyl-phosphine (0.0092 mol) was added, followed by ADDP(0.0092 mol) and the reaction mixture was stirred for 2 hours. Thesolvent was evaporated and the residue was purified by RPhigh-performance liquid chromatography (Hypersil) (eluent: (0.5 NH₄OAcin water)/CH₃CN 90/10). The product fractions were collected and thesolvent was evaporated. The obtained residue was taken up in water andthen the mixture was alkalised with K₂CO₃ and extracted with DCM. Theorganic layer was separated, dried, filtered off and the solvent wasevaporated. The residue (1.1 g) stirred in DIPE and the precipitate wasfiltered off and then dried, yielding 0.976 g of compound 38.

Compound 39 is made on the same way accordingly compound 38.

4,6-ethanediylidene-14H-pyrimido[4,5-b][6,9,12,1]benzotrioxaazacyclohexadecine,18-chloro-8,9,11,12,15,20-hexahydro-21-methoxy- (compound 39) EXAMPLEB32 Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,11]benzoxadiazacyclohexadecin-11(12)-one,18-chloro-9,10,13,14,15,20-hexahydro-21-methoxy- (compound 40)

A mixture of intermediate 177 (0.00045 mol), PyBOP (0.00135 mol) andtriethylamine (0.00135 mol) was reacted for 3 hours at 60° C. and thesolvent was evaporated. The residue was purified by RP high-performanceliquid chromatography, then the product fractions were collected and thesolvent was evaporated, yielding 0.008 g of compound 40.

EXAMPLE B33 a) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecine-10(11H)-carboxylicacid, 19-chloro-8,9,12,13,14,15,16,21-octahydro-22-methoxy-12-oxo-,1,1-dimethylethyl ester (compound 41)

THF p.a. (150 ml) and tributyl-phosphine (0.003 mol) were stirred underN₂ at 50° C. and ADDP (0.003 mol) was added, then a mixture ofintermediate 181 (0.0009 mol) in THF p.a. (15 ml) was added and thereaction mixture was stirred for 2 hours at 60° C. Extratributyl-phosphine (0.003 mol) and ADDP (0.003 mol) were added and theresulting mixture was stirred for 2 hours at 60° C. Finally, the solventwas evaporated, yielding (used as such in the next reaction step)compound 41.

b) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,1-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy- (compound 42)

A mixture of compound 41 (residue) in methanol (50 ml) and2-propanol/HCl (5 ml) was stirred for 72 hours at RT and then thesolvent was evaporated. The residue was taken up in water and washed 3times with DCM. The aqueous layer was alkalised with K₂CO₃ and extractedwith DCM. The crude mixture was then purified on a glass filter (eluent:DCM/CH₃OH/NH₃) 90/10). The product fractions were collected and thesolvent was evaporated, yielding 0.322 g of compound 42.

c) Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[(2-hydroxyethyl)methylamino]acetyl]-22-methoxy-(compound 43)

Compound 42(0.0.000045 mol), DMA (2 ml) and DIPEA (0.00013-mol) werestirred and bromo-acetyl chloride (0.00011 mol) was added dropwise, then2-(methylamino)-ethanol (0.00044 mol) was added and the reaction mixturewas stirred for 16 hours at 60° C., yielding 0.013 g of compound 43.

Following compounds were made accordingly: Compound No. Name 444,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]acetyl]-22-methoxy- 454,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-8,9,10,11,14,15,16,21-octahydro-10-[[2-(hydroxymethyl)-4-morpholinyl]acetyl]-22-methoxy- 46 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[[[2-(4-pyridinyl)ethyl]amino]acetyl]- 47 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-10-[[[2-(dimethylamino)ethyl]methylamino]acetyl]-8,9,10,11,14,15,16,21-octahydro-22-methoxy- 48 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[[(2-methoxyethyl)amino]acetyl]- 49 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[[(3-methoxypropyl)amino]acetyl]- 50 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-(4-morpholinylacetyl)- 514,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one, 19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-10-[(4-methyl-1-piperazinyl)acetyl]-

EXAMPLE B34 Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriaizacycloheptadecin-12(13H)-one,19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy-1-methyl- (compound52)

4-steps reaction procedure Step (I): intermediate 182 (0.0002 mol),DIPEA (0.0008 mol) and DCM (7 ml) was shaken and bromo-acetyl chloride(0.0008 mol) was added, then the reaction mixture was stirred for 3hours and washed 3 times with DCM, to give Resin-(I). Step (II): Resin(I), 2-(methylamino)ethanol (0.0020 mol) and 1-methyl-2-pyrrolidinone (6ml) was shaken for 6 hours at 60° C., then the reaction mixture waswashed [3 times with DMF and 3 times with DCM]×2, to give Resin 4-(II).Step-(III): Resin (II), triphenyl-phosphine (0.0020 mol), ADDP (0.0020mol) and 1-methyl-2-pyrrolidinone (8 ml) was shaken for 6 hours at 60°C., then the reaction mixture was washed 3 times with DMF and 3 timeswith DCM, to give Resin (III). Step (IV): Resin (III) andDCM/TFA/triisopropylsilane (7 ml) was shaken for 16 hours and filtered,then the filter residue was washed and the solvent was evaporated. Theobtained residue was purified by RP high-performance liquidchromatography. The desired product fractions were collected and thesolvent was evaporated, yielding 0.001 g of compound 52.

Following compounds are made on the same way accordingly compound 52:Compound No. Name 53 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacycloheptadecin-12(13H)-one,19-chloro-10-ethyl-8,9,10,11,14,15,16,21- octahydro-22-methoxy- 541,22-ethanediylidene-5H,17H-pyrimido[4,5-b]pyrrolo[2,1-h][6,1,9,12]benzoxatriazacycloheptadecin-14(15H)-one,7-chloro-10,11,12,13,18,19,19a,20-octahydro-24-methoxy- 554,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclooctadecin-13(14H)-one,20-chloro-9,10,11,12,15,16,17,22-octahydro-23-methoxy- 5614H-4,6-ethanediylidene-9,13-methano-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacycloeicosin-15(16H)-one,22-chloro-9,10,11,12,17,18,19,24-octahydro-26-methoxy- 5713H-4,6-ethanediylidene-9,12-ethanopyrimido[4,5-b][6,1,11,14]benzoxatriazacyclononadecin-14(15H)-one,21-chloro-8,9,10,11,16,17,18,23-octahydro-26-methoxy- 5814H-4,6-ethanediylidene-10,13-ethano-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacycloeicosin-15(16H)-one,22-chloro-9,10,11,12,17,18,19,24-octahydro-27-methoxy-

EXAMPLE B35 Preparation of4,6-ethenopyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine-13(8H)-carboxylicacid, 17-bromo-9,10,11,12,14,19-hexahydro-20-methoxy-, phenylmethylester (compound 59)

A mixture of intermediate 114 (0.005 mol) and K₂CO₃ (0.025 mol) in DMA(25 ml) and water (25 ml) was stirred under microwave conditions for 30min. at 150° C. and then the solvent was evaporated under reducedpressure. The obtained residue was stirred in EtOAc and the precipitatewas filtered off. The filtrate was evaporated under reduced pressure andthe residue was purified by column chromatography (eluent: DCM/CH₃OH98/2 to 96/4). The product fractions were collected and the solvent wasevaporated. The obtained residue (1.1 g-38%) was crystallised fromCH₃CN. The resulting precipitate was filtered off and dried. A part ofthis fraction was extra dried, yielding compound 59.

EXAMPLE B36 Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine-12,15-dione;19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy- (compound 60)

A mixture of intermediate 121 (0.00308 mol) in DMF (300 ml) was dropwiseadded overnight to admixture of PyBOP (0.00616 mol) and DIPEA (0.0154mol) in DMF (300 ml), then extra PyBOP (0.00616 mol) and DIPEA (0.0154mol) were added and the reaction mixture was stirred over the weekend.The solvent was evaporated under reduced pressure and the residue wasdissolved in a 10% solution of methanol in DCM and was then washed withwater. The organic layer was separated, dried (MgSO₄), filtered off andthe solvent was evaporated under reduced pressure. The residue waspurified by RP high-performance liquid chromatography. The pure productfractions were collected and then concentrated until precipitationoccurred, yielding compound 60.

EXAMPLE B37 Preparation of4,6-ethenopyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine,17-bromo-16-fluoro-8,9,10,11,12,13,14,19-octahydro-20-methoxy- (compound61)

TFA (2 ml) was added to a mixture of intermediate 127 (0.00055 mol) inDCM (10 ml), then the reaction mixture was stirred for 3 hours at RT andneutralised wit a NaOH solution. The organic layer was separated, dried(MgSO₄), filtered off and the solvent was evaporated. The residue waspurified by column chromatography (gradient eluent: DCM/CH₃OH). The pureproduct fractions were collected and the solvent was evaporated,yielding 0.042 g of compound 61.

EXAMPLE B38 Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-10-[2-(4-morpholinyl)ethyl]-(compound 62)

HBTU (0.00195 mol) was added to a stirred solution of intermediate 130(0.00069 mol) and DIPEA (0.00324 mol) in DMA (250 ml) at RT, then thereaction mixture was stirred for 3 hours and the solvent wasco-evaporated with toluene under reduced pressure. The obtained residuewas purified by RP high-performance liquid chromatography (eluent 1:NH₄OAc; eluent 2: NH₄HCO₃). The pure product fractions were collectedand the solvent was evaporated under reduced pressure. The obtainedresidue (0.030 g) was crystallised from 2-propanol, then the resultingprecipitate was filtered off and dried (vac.), yielding 0.0165 g ofcompound 62.

The following compound 63 was made accordingly;

-   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,    18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-10-(2-methoxyethyl)-    (compound 63).

EXAMPLE B39 Preparation of benzamide,4-fluoro-N-(8,9,10,11,12,13-hexahydro-20-methoxy-4,6-ethanediylidene-19H-pyrimido[4,5-b][6,13,1]benzodioxaazacyclopentadecin-16-yl)-(compound 64)

A solution of intermediate 136 (0.0002 mol) in THF (20 ml) was stirredat Ret and then ADDP (0.0003 mol) and tributyl-phosphine (0.0003 mol)were added. The reaction mixture was stirred for 6 hours at RT and thenextra ADDP (0.0003 mol) and tributyl-phosphine (0.0003 mol) were added.The resulting mixture was stirred for 1 hour and the solvent wasevaporated under reduced pressure. The residue was stirred in methanoland filtered. The filter residue was stirred in boiling 2-propanol, thenthe resulting precipitate was filtered off and stirred in a mixture ofCH₃OH/HCl(1N)/H₂O. After filtration, the filter residue was stirred in aCH₃OH/NH₃ solution and the resulting precipitate was filtered off anddried (vac.) at 60° C., yielding 0.015 g of compound 64.

EXAMPLE B40 Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14-dione,18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-12,12-dimethyl-(compound 65)

A solution of PyBOP (0.0013 mol) and DIPEA (0.0065 mol) in DMA (70 ml)was stirred at RT and then a solution of intermediate 143 (0.0013 mol)in DMA (70 ml) was added dropwise. The reaction mixture was stirred for18 hours at RT and the solvent was evaporated under reduced pressure.The residue was dissolved in DCM and was washed 2 times with a saturatedNaHCO₃ solution and 2 times with water. The organic layer was separated,dried (MgSO₄), filtered off and the solvent was evaporated. The dryresidue was stirred in boiling 2-propanol, then the formed precipitatewas filtered off, washed and dried (vacuum) at 60° C., yielding 0.133 gof compound 65, melting point 285° C.

Following compounds were made according to the synthesis of compound 65:Compound No. Name 66 4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine- 11,14-dione, 18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-12- (1-methylethyl)-melting point:335° C. 67 4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14- dione,18-chloro-9,10,12,13,15,20-hexahydro-21- methoxy-12-(2-methylpropyl)- 684,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine- 12,15-dione,19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-13-(2-methylpropyl)- 694,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-11,14- dione,18-chloro-9,10,12,13,15,20-hexahydro-21- methoxy-melting point: 292° C.

EXAMPLE B41 Preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,10,14]benzoxatriazacycloheptadecin-12(13H)-one,19-chloro-8,9,10,11,14,15,16,21-octahydro-22-methoxy- (compound 70)

DIPEA (0.00930 mol) was added to a solution of intermediate 149 (0.00155mol) in dry DMF (10 ml) and the mixture was stirred for 15 min. thenthis solution was cannulated slowly to a solution of HBTU (0.00465 mol)in DMF (40 ml) and the reaction mixture was stirred for 30 min. Thesolvent was evaporated. The residue was purified by RP high-performanceliquid chromatography. The product fractions were collected and thesolvent was evaporated, yielding 0.258 g of compound 70, melting point236.4-237.3° C.

The following compounds were made accordingly Compound No. Name 714,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 19-chloro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy- melting point 261.2-265°C. 72 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy-13-methyl- melting point288.5-290.5° C. 73 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy- melting point: 294.2-295.2° C. 744,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-14-methyl- melting point:240.0-240.3° C. 75 4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,13]benzoxatriazacyclohexadecin-11(12H)-one, 18-chloro-9,10,13,14,15,20-hexahydro-21-methoxy- melting point: 254.4-256.5° C. 764,6-etheno-8H-pyrimido[4,5-b]pyrrolo[2,1-l][6,1,10,13]benzoxatriazacyclohexadecine-12,15(14H)-dione, 20-chloro-9,10,11,12a,13,17,22-heptahydro-23-methoxy- melting point: 350.5-352.5°C. 77 4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-l][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 20-chloro-8,9,10,11,12a,13,14,15,17,22-decahydro-23-methoxy- melting point:129.8-132.8° C. 78 4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 19-chloro-18-fluoro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy- melting point:261.4-264.0° C. 79 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 17-chloro-16-fluoro-9,10,12,13,14,19-hexahydro-20-methoxy-13-methyl- melting point:306.3-307.4° C. 80 4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-14-methyl- melting point260.4-261.1° C. 81 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 17-chloro-16-fluoro-9,10,12,13,14,19-hexahydro-20-methoxy- melting point 304.2-304.4°C. 82 4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-21-methoxy- melting point: 311.0-311.9°C. 83 4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 19-chloro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy- melting point:262.0-262.8° C. 84 4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-l][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 20-chloro-8,9,10,11,12a,13,14,15,17,22-decahydro-23-methoxy- melting point:231.9-232.8° C. 85 4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 19-chloro-9,10,11a,12,13,14,16,21-octahydro-13-hydroxy-22-methoxy- melting point:279.4-280.7° C. 86 4,6-ethanediylidene-13,16-ethano-8H-pyrimido[4,5-b][6,1,9,12,15]benzoxatetraazacyclooctadecin-11(12H)-one, 20-chloro-9,10,14,15,17,22-hexahydro-25-methoxy- melting point 296.4-297.0° C. 878H-4,6-ethanediylidene-12,15-ethanopyrimido[4,5-b][6,1,9,14]benzoxatriazacycloheptadecin-11(12H)-one, 19-chloro-9,10,13,14,16,21-hexahydro-24-methoxy- melting point: 246.6-248.2° C. 884,6-ethanediylidene-12,16-methano-6H-pyrimido[4,5-b][6,1,9,15]benzoxatriazacyclooctadecin-11(8H)-one, 20-chloro-9,10,12,13,14,15,17,22-octahydro-24-methoxy- melting point: 160-170° C.89 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy-12,13-dimethyl- melting point:265° C. 90 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 17-chloro-13-ethyl-9,10,12,13,14,19-hexahydro-20-methoxy- melting point: 261.1-262°C. 91 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 17-chloro-9,10,12,13,14,19-hexahydro-12-(hydroxymethyl)-20-methoxy- melting point:276.3-277.4° C. 92 4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-l][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 20-chloro-8,9,10,11,12a,13,14,15,17,22-decahydro-14-hydroxy-23-methoxy- meltingpoint: 267.8-268.5° C. 93 4,6-ethanediylidene-14,17-ethanopyrimido[4,5-b][6,1,10,13,16]benzoxatetraazacyclononadecin-12(13H)-one, 21-chloro-8,9,10,11,15,16,18,23-octahydro-26-methoxy- melting point: 286.8-287.6°C. 94 4,6-ethanediylidene-13,16-ethano-6H-pyrimido[4,5-b][6,1,10,15]benzoxatriazacyclooctadecin-12(13H)-one, 20-chloro-8,9,10,11,14,15,17,22-octahydro-25-methoxy- melting point: 253.1-255.9°C. 95 12H-4,6-ethanediylidene-13,17-methanopyrimido[4,5-b][6,1,10,16]benzoxatriazacyclononadecin-12-one, 21-chloro8,$$,10,11,13,14,15,16,18,23-decahydro-25-methoxy- melting point:240.1-242.8° C. 96 4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-13,14-dimethyl- meltingpoint: 241.9-243.0° C. 97 4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-14-ethyl-8,9,10,11,13,14,15,20-octahydro-21-methoxy- melting point: 212.8-214.0°C. 98 4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-8,9,10,11,13,14,15,20-octahydro-13-(hydroxymethyl)-21-methoxy- meltingpoint: 287.6-288.3° C. 99 4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy- melting point: 304.6-304.8°C. 166 4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one, 19-chloro-15-ethyl-9,10,11,12,14,15,16,21-octahydro-22-methoxy- 1674,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one, 19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxy-14,15-dimethyl-

EXAMPLE B42 Preparation of4,6-ethanediylidenepyrimido[4,5]pyrrolo[2,1-m][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,21-chloro-9,10,11,12,13a,14,15,16,18,23-decahydro-24-methoxy- (compound100)

A solution of intermediate 156 (0.0005 mol) and DIPEA (0.003 mol) wasadded to a solution of HBTU (0.0015 mol) and 1-hydroxy- 1H-benzotriazole(0.001 mol) in DMF dry (125 ml) and then the reaction mixture wasreacted for 1 hour. The solvent was evaporated and the dry residue waspurified by RP high-performance liquid chromatography. The productfractions were collected, sodium carbonate was added and the organicsolvent was evaporated. DCM was added to the aqueous concentrate and theresulting mixture was extracted 3 times with DCM, then the organicextract was dried and collected, yielding 0.0394 g (16%) of compound100, melting point 226.3-227.7° C.

The following compounds were made accordingly;

-   4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxy-(compound 101)    melting point: 286.7-287.2° C.-   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-m][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one,    21-chloro-20-fluoro-9,10,11,12,13a,14,15,16,18,23-decahydro-24-methoxy-(compound    102), melting point: 234.7-236.8° C.

EXAMPLE B43 Preparation of4,6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo[2,1-1][6,1,10,13]benzoxatriazacyclohexadecin-12-one,20-chloro-19-fluoro-8,9,10,11,12a,13,14,15,17,22-decahydro-23-methoxy-(compound 103)

A solution of intermediate 162 (0.001 mol) and DIPEA (1.034 ml) in DMF(20 ml) was added to a solution of PyBOP (0.003 mol) and1-hydroxy-1H-benzotriazole (0.001 mol) in DMF (200 ml) and then thereaction mixture was purified by RP high-performance liquidchromatography (CH₃CN/NH₄OAc buffer). The product fractions werecollected, sodium carbonate was added and the organic solvent wasevaporated (precipitation). The aqueous concentrate was cooled in thefridge, then filtered and washed with water, yielding: 0.2087 g (43%) ofcompound 103 melting point 241.6-242.6° C.

The following compound was made accordingly;

-   4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecine-11(8H)-thione,    19-chloro-18-fluoro-9,10,11a,12,13,14,16,21-octahydro-22-methoxy-    (compound 104)

melting point: 211.3-212.7° C.

EXAMPLE B44 a) preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,16]benzoxadiazacyclononadecin-16(17H)-one,21-chloro-8,9,10,13,14,15,18,23-octahydro-24-methoxy- (B) (compound 105)and

-   4,6-ethanediylidenepyrimido[4,5-b][6,1,16]benzoxadiazacyclononadecin-16(17H)-one,    21-chloro-8,9,10,13,14,15,18,23-octahydro-24-methoxy- (A) (compound    106)

A mixture of intermediate 165 (0.000424 mol) and Grubbs II catalyst(0.000042) in DCM (200 ml; degassed) was stirred for 6 hours at RT andunder N₂, then the solvent was evaporated and the residue was purifiedby RP high-performance liquid chromatography. Two product fractions werecollected and the solvent was evaporated, yielding 0.046 g (23.3%) ofcompound 106 (A) and 0.078 g (39.5%) of compound 105(B).

b) preparation of4,6-ethanediylidenepyrimido[4,5-b][6,1,16]benzoxadiazacyclononadecin-16(17H)-one,21-chloro-8,9,10,1,1-12,13,14,15,18,23-decahydro-24-methoxy- (compound107)

A mixture of compound 105 (0.000064 mol) in TAP (15 ml) and methanol (15ml) was hydrogenated for 3 hours with Pt/C 5% (0.03 g) as a catalyst.After uptake of H₂ (1 equiv.), the catalyst was filtered off and thefiltrate was evaporated, yielding compound 107.

The following compounds were made accordingly;

-   4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-15(16H)-one,    20-chloro-9,12,13,14,17,22-hexahydro-23-methoxy- (compound 108).

EXAMPLE B45 a) Preparation of carbamic acid,(20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxy-15-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b)[6,1,15]benzoxadiazacyclooctadecin-14-yl)-,1,1-dimethylethyl ester (A) (compound 109) and Preparation of carbamicacid,(20-chloro-9,10,13,14,15,16,17,22-octahydro-23-methoxy-15-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-14-yl)-,1,1-dimethylethyl ester (B) (compound 110)

A solution of intermediate 169 (0.0015 mol) and Grubbs II catalyst(0.00015) in DCM (150 ml) was stirred overnight at RT, then the solventwas evaporated and the residue was purified by RP high-performanceliquid chromatography. Two product fractions were collected and thesolvent was evaporated, yielding 0.110 g of compound 109 (A) and 0.064 gof compound 110 (B).

b) Preparation of carbamic acid,(20-chloro-9,10,11,12,13,14,15,16,17,22-decahydro-23-methoxy-15-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-14-yl)-,1,1-dimethylethyl ester (compound 111)

A mixture of compound 109 (0.00025 mol) in THF (15 ml) and methanol (15ml) was hydrogenated for 3 hours with Pt/C 5% (0.1 g) as a catalyst.After uptake of H₂ (1 equiv.), the catalyst was filtered off and thefiltrate was evaporated. The residue was filtered over silica gel withDCM/CH₃OH (10/1) and the filtrate was evaporated, then the obtainedresidue was crystallised from methanol and the resulting solids werecollected, yielding compound 111.

Following compound was made accordingly:

-   carbamic acid,    (18-chloro-11,12,13,14,15,20-hexahydro-21-methoxy-13-oxo-4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,13]benzoxadiazacyclohexadecin-12-yl)-,    1,1-dimethylethyl ester (compound 165)

c) Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-15(16H)-one,14-amino-20-chloro-9,10,11,12,13,14,17,22-octahydro-23-methoxy- HCl(1:2) (compound 112)

6N HCl in 2-propanol (5 ml) was added to a solution of compound 111(0.000088 mol) in ThF (q.s.) and the reaction mixture was stirred for 1hour at RT and then the solvent was evaporated, yielding 0.050 g ofcompound 112, isolated as a hydrochloric acid salt.

d) Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,15]benzoxadiazacyclooctadecin-15(161)-one,20-chloro-14-(dimethylamino)-9,10,11,12,13,14,17,22-octahydro-23-methoxy-(compound 113)

A mixture of compound 112 (0.000085 mol) and formaldehyde (0.00052 g) inmethanol (2 ml) was hydrogenated with Pt/C 5% (0.04 g) as a catalyst inthe presence of thiophene solution (0.04 ml). After uptake of H₂ (2equiv.), the catalyst was filtered off and the filtrate was evaporated.The obtained residue was purified by RP high-performance liquidchromatography, then the product fractions were collected and thesolvent was evaporated, yielding compound 113.

EXAMPLE B46 Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecine,18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxy-14-methyl-(compound 114)

A solution of intermediate 186 (0.00095 mol) in dioxane (10 ml), water(5 ml) and HCl concentrated (5 ml) was stirred for 27 hours at 50° C.and then the reaction mixture was poured out into a saturated aqueousNaHCO₃ solution and extracted with DCM. The organic extract was thendried and filtered over potassium carbonate. NaBH(OAc)₃ (0.00095 mol)was immediately added. The reaction mixture was stirred for 1 hour atRT. The mixture was purified by RP high-performance liquidchromatography, then the product fractions were collected and thesolvent was evaporated, yielding 0.6576 g of compound 114, melting point202.8-203.6° C.

The following compounds were made accordingly; Compound No. Name 1154,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine, 19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxy-15- methyl-meltingpoint: 196.9-197.8° C. 116 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine,17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13- methyl-meltingpoint: 195.8-196.6° C. 117 4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine, 20-chloro-9,10,11,12,13,14,15,16,17,22-decahydro-23-methoxy- 16-methyl-

EXAMPLE B47 Preparation of4,6-ethanediylidenepyrimido[4,5-b](6,1,12]benzoxadiazacyclopentadecine,17-chloro-8,9,12,13,14,19-hexahydro-20-methoxy-13-methyl- ±75% E and±25% Z (compound 118)

Grubbs II catalyst (a total of 0.0012 mol) was added in several portionsto a solution of intermediate 191 (0.0016 mol) in DCM (100 ml) and thereaction mixture was stirred and refluxed for a total of 4 days. Theobtained mixture was purified 2 times by RP high-performance liquidchromatography. The product fractions were collected and the solvent wasevaporated, yielding 0.0116 g of compound 118.

Preparation of4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione,18-chloro-10,11,13,14,15,20- hexahydro-21-methoxy-11-methyl-hydrate(1:1) (compound 119)

A mixture of intermediate 197 (0.0010 mol) and DIPEA (0.0040 mol) in DMFdry (50 ml) was slowly added to a solution of1-[bis(dimethylamino)methylene]-1H-benzotriazolium, hexafluorophosphate(1-), 3-oxide (0.0025 mol) in DMF dry (200 ml) at RT, then the reactionmixture was quenched with water (5 ml) and the solvent was evaporated.The obtained residue was purified by RP high-performance liquidchromatography. The product fractions were collected and the organicsolvent was evaporated, yielding 0.024 g of compound 119.

The following compounds were made accordingly; Compound No. Name 1204,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-20-methoxy-11-methyl- 1214,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-20-methoxy-11-(1-methylethyl)- 1224,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-20-methoxy-11-(phenylmethyl)- 1234,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,10,11,14,19-tetrahydro-20-methoxy-11-methyl- 1244,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,10,11,14,19-tetrahydro-20-methoxy-11-(1-methylpropyl)- 1259,11-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclopentadecine-14,19(5H,13H)-dione,16,17,18,18a,20,21-hexahydro-22-methoxy- 1269,11-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclopentadecine-14,19(5H,13H)-dione, 3-chloro-16,17,18,18a,20,21-hexahydro-22-methoxy- 1274,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-11-(1-hydroxyethyl)-20-methoxy- 1284,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-(1-methylpropyl)- 1294,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-11-(hydroxymethyl)-20-methoxy- 1304,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-13-(hydroxymethyl)-22-methoxy- 1314,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-methyl- 1324,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-20-methoxy-11,11-dimethyl- 1339,11-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclopentadecine-14,19(5H,13H)-dione, 3-chloro-16,17,18,18a,20,21-hexahydro-17-hydroxy-22-methoxy- 1344,6-ethanediylidene-8H-pyrimido[4,5-b]pyrrolo[1,2-l][6,1,12,15]benzoxatriazacyclooctadecine-12,17(18H)-dione, 22-chloro-9,10,11,14,15,16,16a,19,24-nonahydro-25-methoxy- 1354,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione, 18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy-11,11-dimethyl- 1364,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione, 20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14-(2-methylpropyl)- 1374,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione, 20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14,14-dimethyl- 1384,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione, 20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14-(phenylmethyl)- 1394,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione, 20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-14-methyl- 1401,21-ethanediylidene-5H-pyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclohexadecine-13,18(19H)-dione, 7-chloro-10,11,12,13a,14,15,16-heptahydro-23-methoxy- 1414,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione, 18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy-11-(2-methylpropyl)- 1424,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione, 18-chloro-10,11,13,14,15,20-hexahydro-11-(1-hydroxyethyl)-21-methoxy- 1434,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-(2-methylpropyl)- 1444,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13,13-dimethyl- 1454,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13-(phenylmethyl)- 1464,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-13-(1-hydroxyethyl)-22-methoxy- 1474,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione, 20-chloro-9,10,11,13,14,17,22-heptahydro-14-(1-hydroxyethyl)-23-methoxy- 1484,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione, 18-chloro-10,11,13,14,15,20-hexahydro-11-(hydroxymethyl)-21-methoxy- 1491,21-ethanediylidene-5H-pyrimido[4,5-b]pyrrolo[1,2-i][6,1,9,12]benzoxatriazacyclohexadecine-13,18(19H)-dione, 7-chloro-10,11,12,13a,14,15,16-heptahydro-15-hydroxy-23-methoxy-

EXAMPLE B49 Preparation of4,6-ethenopyrimido[4,5-b][6,1,9,14]benzoxatriazacycloheptadecine-9,14(8H,15H)-dione,19-chloro-10,11,12,13,16,21-hexahydro-22-methoxy- (compound 150)

Intermediate 122 (0.001 mol) and DIPEA (0.004 mol) were added to amixture of PyBOP (0.003 mol) in DMF (250 ml) and the reaction mixturewas stirred for 2 hours, then water was added and the solvent wasevaporated. The obtained residue was purified by RP high-performanceliquid chromatography. The product fractions were collected and theorganic solvent was evaporated. The aqueous concentrate was allowed toprecipitate overnight in the fridge and the resulting solids were thenfiltered off, yielding 0.093 g (20%) of compound 150.

The following compounds were made accordingly; Compound No. Name 1514,6-ethenopyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-20-methoxy- 1524,6-etheno-8H-pyrimido[4,5-b][6,1,9,13]benzoxatriazacyclohexadecine-9,13(10H,14H)-dione, 18-chloro-11,12,15,20-tetrahydro-21-methoxy- 1534,6-ethenopyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine-11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-154 4,6-ethenopyrimido[4,5-b][6,1,11,16]benzoxatriazacyclononadecine-11,16(8H,17H)-dione, 21-chloro-9,10,12,13,14,15,18,23-octahydro-24-methoxy- 1554,6-etheno-8H-pyrimido[4,5-b][6,1,11,15]benzoxatriazacyclooctadecine-11,15(12H,16H)-dione, 20-chloro-9,10,13,14,17,22-hexahydro-23- methoxy-156 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione,10,11,14,19-tetrahydro-20-methoxy- 1574,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,13]benzoxatriazacyclohexadecine-9,13(10H,14H)-dione,11,12,15,20-tetrahydro-21-methoxy- 158 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,14]benzoxatriazacycloheptadecine-9,14(8H,15H)-dione,10,11,12,13,16,21-hexahydro-22-methoxy- 1594,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine-9,12(8H,13H)-dione, 17-chloro-10,11,14,19-tetrahydro-20-methoxy-10-methyl- 1604,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione, 18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy- 1614,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,14]benzoxatriazacyclooctadecine-9,14-dione, 20-chloro-10,11,12,13,15,16,17,22-octahydro-23-methoxy- 1624,6-ethanediylidenepyrimido[4,5-b][6,1,12,16]benzoxatriazacyclononadecine-12,16(13H,17H)-dione, 21-chloro-8,9,10,11,14,15,18,23-octahydro-24-methoxy- 1634,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,17]benzoxatriazacycloeicosine-12,17(18H)-dione, 22-chloro-9,10,11,13,14,15,16,19,24-nonahydro-25-methoxy- 1644,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,9,12]benzoxatriazacyclohexadecine-9,12-dione, 18-chloro-10,11,13,14,15,20-hexahydro-21-methoxy-10-methyl- 1684,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,12,15]benzoxatriazacyclooctadecine-12,15(16H)-dione, 20-chloro-9,10,11,13,14,17,22-heptahydro-23-methoxy-13-methyl-Compound Identification

The compounds were identified by LC/MS using a gradient elution systemon a reversed phase HPLC. The compounds are identified by their specificretention time and their protonated molecular ion MH⁺ peak. The TALCgradient was supplied by a Waters Alliance HT 2790 system with a columnheater set at 40° C. Flow from the column was split to a Waters 996photodiode array (PDA) detector and a Waters-Micromass ZQ massspectrometer with an electrospray ionization source operated in positiveand negative ionization mode. Reversed phase HPLC was carried out on aXterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of 16 ml/min.Three mobile phases (mobile phase A 95% 25 mM ammoniumacetate+5%acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol)were employed to run a gradient condition from 100% A to 50% B and 50% Cin 6.5 minutes, to 100% B in 1 minute, 100% B for 1 minute andreequilibrate with 100% A for 1.5 minutes. An injection volume of 10 μLwas used.

Mass spectra were acquired by scanning from 100 to 1000 in is using adwell time of 0.1 s. The capillary needle voltage was 3 kV and thesource temperature was maintained at 140° C. Nitrogen was used a thenebulizer gas. Cone voltage was 10 V for positive ionization mode and 20V for negative ionization mode. Data acquisition was performed with aWaters-Micromass MassLynx-Openlynx data system. TABLE retention time (RTin minutes) and molecular weight as the MH⁺ Compound Compound No. Rt MH⁺No. Rt MH⁺ 64 6.38 503 121 4.32 470 38 6.64 414 122 4.84 518 40 4.93 42760 4.53 456 71 5.66 454 123 3.05 408 150 3.84 454 124 4.08 450 153 3.89546 125 3.56 434 120 3.77 442 156 2.83 394 157 3.01 408 168 4.17 484 1583.3 422 136 4.62 526 126 4.33 468 137 4.18 498 159 4.02 442 138 4.62 560127 3.62 472 139 3.88 456 128 5.34 512 119 4.5 456 129 3.47 458 140 5.03482 130 3.93 486 164 4.74 456 131 4.34 470 141 5.41 498 160 4.04 442 1424.17 486 161 3.86 470 143 5.16 512 106 8.73 467 144 4.42 484 105 9.6 467145 5.18 546 132 3.74 456 147 4.3 514 133 3.63 484 110 6.2 568 108 6.09453 109 6.14 568 117 5.95 456 148 3.92 472 63 4.75 500 149 4.45 498 1624 484 111 6.26 570 163 3.91 498 165 5.82 540 134 4.51 510 135 4.56 470

C. Pharmacological Examples EXAMPLE C1 In Vitro Inhibition of EGFR Usinga Scintillant Proximity Assay

In the present EGFR SPA kinase reaction assay, a kinase substrateconsisting of biotinylated poly(L-glutamic acid-L-tyrosine)(poly(GT)biotin), is incubated with the aforementioned protein in thepresence of (³³P) radiolabeled ATP. (³³P) phosporylation of thesubstrate is subsequently measured as light energy emitted usingstreptavidin-coated SPA beads (Amersham Pharmacia Biotech) by trappingand quantifying the binding of the biotin tagged and radiolabeledsubstrate.

Detailed Description

The EGFR SPA kinase reaction is performed at 30° C. for 60 minutes in a96-well microtiter plate. For each of the tested compounds a full doseresponse 1.10⁻⁶M to 1.10⁻¹⁰M has been performed. IRESSA® and Tarceva™(erlotinib) were used as reference compounds. The 100 μl reaction volumecontains 54.5 mM Tris HCl pH 8.0, 10 mM MgCl₂, 100 μM Na₃VO₄, 5.0 μMunlabeled ATP, 1 mM DTT, 0.009% BSA, 0.8 μCi ³³P-ATP, 0.35 μg/wellpoly(GT)biotin and 0.5 μg EGFR-kinase domain/well. The reaction isstopped by adding to each well 100 μl of the streptavidin beads (10mg/ml in PBS+100 mM EDTA+100 μM ATP). The plates are than shaked at 300rpm for 30 min to allow binding of the biotinylated substrate to thestreptavidin coated beads. Than the beads are allowed to settle at thebottom of the plate for 30 minutes. The microtiterplates are centrifugesat 800 rpm for 10 minutes and the amount of phosphorylated (³³)Poly(GT)biotin is determined by counting (30 sec/well) in amicrotiterplate scintillation counter.

EXAMPLE C.2 In Vitro Inhibition of EGFR

The in vitro inhibition of EGFR was assessed using either the FlashPlate technology or the glass-fiber filter technology as described byDavies, S. P. et al., Biochem J. (2000), 351; p. 95-105. The Flash Platetechnology is generally described by B. A. Brown et al. in HighThroughout Screening (1997), p. 317-328. Editor(s): Devlin, John P.Publisher: Dekker; New York, N.Y.

In the Flash Plate EGFR kinase reaction assay, a kinase substrateconsisting of biotinylated poly(L-glutamic acid-L-tyrosine)(poly(GT)biotin), is incubated with the aforementioned protein, in thepresence of (³³P) radiolabeled ATP-. (³³P) phosporylation of thesubstrate is subsequently measured as light energy emitted using astreptavidin-coated Flash Plate (PerkinElmer Life Sciences) by trappingand quantifying the binding of the biotin tagged and radiolabeledsubstrate.

Detailed Description

The EGFR kinase reaction is performed at 30° C. for 60 minutes in a96-well microtiter FlashPlate (PerkinElmer Life Sciences). For each ofthe tested compounds a full dose response 1.10⁻⁶ to 1.10⁻¹⁰M has beenperformed. IRESSA® and Tarceva™ (erlotinib) were used as referencecompounds. The 100 μl reaction volume contains 54.5 mM Tris HCl pH 8.0,10 mM MgCl₂, 100 μM Na₃VO₄, 5.0 μM unlabeled ATP, 1 mM DTT, 0.009% BSA,0.8 μCi AT³³P, 0.35 μg/well poly(GT)biotin and 0.5 μg EGFR-kinasedomain/well.

The reaction is stopped by aspirating the reaction mixture and washingthe plate 3× with 200 μl wash/stop buffer (PBS+100 mM EDTA). After thefinal wash step 200 μl of wash/stop buffer was added to each well andthe amount of phosphorylated (³³P) Poly(GT)biotin determined by counting(30 sec/well) in a microtiterplate scintillation counter.

In the glass-fiber filter technology EGFR kinase reaction assay, akinase substrate consisting of poly(L-glutamic acid-1-tyrosine)(poly(GT)), is incubated with the aforementioned protein in the presenceof (³³P) radiolabeled ATP. (³³P) Phosporylation of the substrate issubsequently measured as radioactivity bound on a glassfiber-filter.

Detailed Description

The EGFR kinase reaction is performed at 25° C. for 10 minutes in a96-well microtiterplate. For each of the tested compounds a full doseresponse 1.10⁻⁶M to 1.10⁻¹⁰M has been performed. IRESSA® and Tarceva™(erlotinib) were used as reference compounds. The 25 μl reaction volumecontains 60 mM Tris HCl pH 7.5, 3 mM MgCl₂, 3 mM Mn Cl₂, 3 μM Na₃VO₄, 50μg/ml PEG20000, 5.0 μM unlabeled ATP, 1 mM DTT, 0.1 μCi AT³³P, 62.5ng/well poly(GT) and 0.5 μg EGFR-kinase domain/well.

The reaction is stopped by adding 5 μl of a 3% phosphoric acid solution.10 μl of the reaction mixture is then spotted onto a Filtermat A filter(Wallac) and washed 3 times for 5 min. in 75 mM phosphoric acid and 1time for 5 min. in methanol prior to drying and quantification on theTyphoon (Amersham) using a LE phosphorage storage screen.

EXAMPLE C.3 Serum Starved Proliferation Assay on the Ovarian CarcinomaSKOV3 Cells

The ovarian carcinoma cell line (SKOV3) was used in an epidermal growthfactor stimulated cell proliferation assay, to assess the inhibitoryeffect of the compounds on EGF in whole cells.

In a first step the SKOV3 cells were incubated for 24 hours in thepresence of 10% FCS serum. In the second step the cells were incubatedwith the compounds to be tested in a serum free condition (37° C. and 5%(v/v) CO₂) and subsequently stimulated for 72 hours with EGF at a finalconcentration of 100 ng/ml. The effect of the compounds on the EGFstimulation was finally assessed in a standard MIT cell viability assay.

Alternatively, the SKOV3 cells were incubated for 24 hours in thepresence of 10% FCS serum. In the second step the cells were incubatedfor 72 hours with the compounds to be tested and the effect of thecompounds on cell proliferation was finally assessed in a standard MTTcell viability assay.

EXAMPLE C.4 ELISA Assay of EGFR Tyrosine Kinase Activity

The EGFR ELISA is generally described by Yang, E. B. et al., 2001,Biochimica et Biophysica Acta, 1550; 144.

For the determination of EGFR tyrosine kinase activity, 100 μl of 0.4μg/ml poly(Glu, Tyr) in PBS was coated per well on a 96-well microplateat 37° C. overnight. The non-specific binding sites were subsequentlyblocked by incubation for 30 minutes at room temperature with 200 μl BSAdilution (10 mg/ml in PBS) per well. After washing three times with PBSthe plates were either used immediately or stored at 4° C.

Prior to the determination of the EGFR tyrosine kinase activity, thecoated plates were washed two times with PBS. Next, to each well 88 μlof an ATP dilution (50 mM Tris HCl pH 8.0, 10 mM MgCl₂, 100 μM Na₃VO₄, 1mM DTT, 5 μM ATP) and 2 μl with various concentrations of the compoundsto be tested, were added. The EGFR tyrosine kinase-catalysed reactionwas started by the addition of −10 μl of diluted EGFR tyrosine(dilution→0.05 μg per well enzyme diluted in 50 mM Tris HCl pH 8.0+0.1%BSA).

After incubation at room temperature for 10 min, the reaction wasstopped by washing five times with PBS with 0.1% Tween 20. Subsequently100 ml of recombinant anti-phosphotyrosine horseradish peroxidaseconjugate (1:2500) in BSA (10 mg/ml in PBS) was added. After incubationat room temperature for 1 h, the microplate was washed five times withPBS/Tween 20. After the microplate was incubated with 100 μl ofTMB-ELISA (1-step Ultra TMB-ELISA, Pierce) until colour development, 100μl of 0.5 M H₂SO₄ was added to stop the reaction, and it was read in amicroplate reader at 450-655 nm.

EXAMPLE C.5 Proliferation Assay on the Squamous Carcinoma Cell Line A431Cells

The squamous carcinoma cell line (A431) was used in a cell proliferationassay, to assess the inhibitory effect of the compounds in whole cells.

In a first step the A431 cells were incubated for 24 hours in thepresence of 10% FCS serum. In the second step the cells were incubatedfor 72 hours with the compounds to be tested at a final concentration of100 ng/ml. The effect of the compounds on the cell proliferation wasfinally assessed in a standard MTT cell viability assay.

The following tables provides the IC50 values of the compounds accordingto the invention, obtained using the above mentioned kinase assays.Compound EGFR SPA (C1): Kinase activity.(C2): SKOV3 cell (C3): A431 cellEGFR ELISA number IC50 in nM pIC50 pIC50 (C5): pIC50 (C4): IC50 in nM 1 >100 <5.0 <5.7 <6.0 >1000  2 >100 7.0 <5.7 <6.0 >1000  3 3.61 7.85.87 <6.0 >1000  4 32.58 7.3 5.54 NT 556  5 81.10 6.4 5.32 NT >1000  64.40 7.6 5.74 NT 359  7 6.64 7.1 <5 NT >1000  8 3.97 7.5 <5 NT 329  96.79 7.4 NT NT >1000 16 NT 5.6 NT NT >1000 18 NT 7.1 <5 NT >1000 17 NT7.4 5.08 5.6 269 10 NT 7.3 <5 <5.5 >1000 12 NT <5 <5 <5.5 >1000 14 NT <5<5 <5.5 >1000 11 NT <5 <5 <5.5 >1000 13 NT 6.5 <5 <5.5 >1000 20 NT 7.66.64 5.9 NT 19 NT 7.2 5.3 <5.5 NT 21 NT 8.0 6.09 <5.5 158 22 NT 7.8 6.595.8 38.4 23 NT 8.0 7.22 6.3 NT 24 NT 7.7 5.5 <5.5 NT 25 NT 6.2 <5 <5.5NT 26 NT 8.6 6.92 5.7 NT 28 NT 7.6 5.84 5.8 NT 29 NT 6.1 <5 <5.5 NT 30NT 7.5 5.99 <6.0 NT 32 NT 8.4 6.54 NT NT 33 NT 7.6 5.76 5.8 NT 34 NT 7.2<5 <5.5 NT 35 NT 5.4 <5 <5.5 NT 36 NT 7.8 6.78 <5.5 NT 37 NT <5 <5 <5.5NT 38 NT 7.7 6.9 5.9 NT 39 NT 7.7 6.7 5.8 NT 40 NT 7.5 7.3 6.2 NT KinaseKinase Compound activity.(C2): SKOV3 cell Example Compoundactivity.(C2): SKOV3 cell Example number pIC50 (C3): pIC50 number numberpIC50 (C3): pIC50 number  64 6.0 6.4 B39 150 7.7 5.1 B49  71 7.5 5.5 B41152 7.5 5.0 B49  72 6.8 5.0 B41 153 7.8 6.1 B49  73 7.4 5.4 B41 154 7.45.6 B49  74 7.6 6.0 B41 155 6.5 6.0 B49  75 7.2 5.2 B41  61 7.8 6.4 B39 70 8.0 5.5 B41 120 5.7 6.0 B48 151 5.5 5.0 B49 121 5.6 5.0 B48  76 7.66.7 B41 122 6.4 5.0 B48  77 7.8 6.1 B41  66 7.1 8.0 B40  65 7.9 7.7 B40158 5.3 5.0 B49  67 7.0 6.3 B40  78 7.5 6.5 B41  68 7.9 8.2 B40 114 8.07.4 B46  69 7.3 7.2 B40  79 6.2 5.0 B41  60 7.8 8.7 B36  80 7.7 7.2 B41123 5.2 5.0 B48  81 6.6 6.6 B41 124 5.0 5.0 B48  82 7.7 7.1 B41 125 5.15.0 B48  99 7.6 6.7 B41 156 5.0 5.0 B49 126 5.7 5.6 B48 157 5.0 5.0 B49159 6.5 5.7 B49 127 6.6 5.8 B48 101 6.6 7.5 B42 128 8.0 6.7 B48  52 7.17   B34 129 5.8 5.4 B48  53 6.7 6.3 B34 130 7.6 6.9 B48  54 6.9 5.9 B34131 7.6 7.0 B48  55 6.3 6.7 B34 160 7.2 6.2 B49  56 5.8 5.0 B34 161 7.25.9 B49  57 5.2 6.4 B34  83 6.3 6.1 B41  58 5.7 5.7 B34  84 6.2 6.5 B41 44 6.2 5.1 B33 103 7.2 7.3 B43  45 6.8 5.0 B33  42 6.3 7.2 B33 106 7.07.2 B44  43 7.1 6.3 B33 105 6.8 7.6 B44  46 6.7 5.1 B33 104 6.0 6.5 B43 47 6.9 5.8 B33 115 8.2 6.9 B46  48 6.5 5.8 B33 116 6.7 7.2 B46  49 6.46.1 B33 132 5.0 5.0 B48  50 7.1 6.8 B33 133 5.8 5.1 B48  51 6.4 B33 1086.4 6.8 B44 100 8.1 6.9 B42 117 6.7 5.4 B46 102 6.7 7.3 B42  63 6.9 5.7B38 162 6.8 7.3 B49 164 6.3 6.8 B49 163 7.0 6.4 B49 141 6.1 5.8 B48 1346.4 6.1 B48 142 7.0 6.2 B48 135 5.4 6.0 B48 143 6.3 6.7 B48 136 6.2 6.6B48 144 6.8 6.9 B48 137 6.6 6.6 B48 145 6.7 6.6 B48 138 5.7 6.2 B48 1466.7 6.2 B48 139 6.4 6.8 B48 147 6.9 6.6 B48 119 6.0 5.8 B48  62 6.4 5.3B48 140 6.7 6.7 B48 110 5.4 5.0 B45 109 5.7 6.5 B45 111 5.8 5.0 B45 1486.6 5.0 B48 149 6.9 5.8 B48D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic administration to animal and human subjects inaccordance with the present invention.

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of formula a) of a pharmaceutically acceptable addition saltthereof.

EXAMPLE D.1 Film-Coated Tablets Preparation of Tablet Core

A mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixedwell and thereafter humidified with a solution of sodium dodecyl sulfate(5 g) and polyvinyl-pyrrolidone (10 g) in about 200 ml off water. Thewet powder mixture was sieved, dried and sieved again. Then there wasadded microcrystalline cellulose (100 g) and hydrogenated vegetable oil(15 mg). The whole was mixed well and compressed into tablets, giving10.000 tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of methylcellulose (10 g) in denaturated ethanol (75 ml)there was added a solution of ethyl cellulose (5 g) in DCM (150 ml).Then there were added DCM (75 ml) and 1,2,3-propanetriol (2.5 ml).Polyethylene glycol (10 g) was molten and dissolved in dichloromethane(75 ml). The latter solution was added to the former and then there wereadded magnesium octadecanoate (2.5 g), polyvinyl-pyrrolidone (5 g) andconcentrated color suspension (30 ml) and the whole was homogenated. Thetablet cores were coated with the thus obtained mixture in a coatingapparatus.

1. A compound having the formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents O, CH₂, NH or S; Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₃₋₉alkynyl-, —C₃₋₇alkyl-CO—NH— optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-, —C₃₋₇alkenyl-CO—NH— optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-, —C₃₋₇alkynyl-CO—NH— optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—, —C₁₋₃alkyl-NH—CS-Het²⁰-, —C₁₋₃alkyl-NH—CO-Het²⁰-, C₁₋₂alkyl-CO-Het²¹-CO—, -Het²²-CH₂—CO—NH—C₁₋₃alkyl-, —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO—, —C₁₋₆alkyl-CO—C₁₋₆alkyl-, —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—, —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—, —C₁₋₂alkyl-NR²¹—CH₂—CO—NH—C₁₋₃alkyl-, or —NR²²—CO—C₁₋₃alkyl-NH—; X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹¹, —NR¹¹—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-; X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-; R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-, C₁₋₆alkyl-, halo-phenyl-carbonylamino-, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl, C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR⁵R⁶, C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C₁₋₄alkyl-oxy-; R³ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one or more substituents selected from halo, C₁₋₄alkyloxy-, amino-, mono- or di(C₁₋₄alkyl)amino-, C₁₋₄alkyl-sulfonyl- or phenyl; R⁴ represents hydrogen, hydroxy, Ar³-oxy, Ar⁴—C₁₋₄alkyloxy-, C₁₋₄alkyloxy-, C₂₋₄alkenyloxy- optionally substituted with Het¹² or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy-, hydroxy, halo, Het²-, —NR⁷R⁸, -carbonyl- NR⁹R¹⁰ or Het³-carbonyl-; R⁵ and R⁶ are each independently selected from hydrogen or C₁₋₄alkyl; R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl, Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl, Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-, Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-; R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-; R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶—C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl-optionally substituted with Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁸-C₁₋₄alkyl-, phenyl-C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷, C₂₋₄alkenylcarbonyl- optionally substituted with Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or R¹² represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴—C₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹⁴ and R¹⁵ are each independently selected from hydrogen, C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-; R¹⁶ and R¹⁷ each indepedently represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R¹⁸ and R¹⁹ each indepedently represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R²⁰ and R²² each independently represents hydrogen or C₁₋₄alkyl optionally substituted with hydroxy or C₁₋₄alkyloxy; R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or R²¹ represents mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C₁₋₄alkyloxy; Het¹ represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het¹ is optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-, mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-; Het³, Het⁴ and Het⁸ each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or Het⁸ is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-, C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-; Het⁵ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁶ and Het⁷ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁹ and Het¹⁰ each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or amino-C₁₋₄alkyl-; Het¹¹ represents a heterocycle selected from indolyl or

Het¹² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het¹² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-; Het¹³ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁴ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁵ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁶ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C₁₋₄alkyl; and Het¹⁷ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het²⁰, Het²¹ and Het²² each independently represent a heterocycle selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from hydroxy, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-; Het²³ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl optionally substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl, aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.
 2. A compound according to claim 1 wherein; Z represents O, NH or S; Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—, —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO—, —C₁₋₆alkyl-CO—C₁₋₆alkyl-, —C₁₋₂alkyl-NH—CO—CH₂R¹⁶—NH—; X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹¹, —NR¹¹—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-; X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹², NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-; R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-, C₁₋₆alkyl, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl, C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR⁵R⁶, C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C₁₋₄alkyl-oxy-; R³ represents hydrogen, C₁₋₄alkyl or C₁₋₄alkyl substituted with one or more substituents selected from halo, C₁₋₄alkyloxy-, amino-, mono- or di(C₁₋₄alkyl)amino-, C₁₋₄alkyl-sulfonyl- or phenyl; R⁴ represents hydrogen, hydroxy, Ar³-oxy, Ar⁴—C₁₋₄alkyloxy-, C₁₋₄alkyloxy-, C₂₋₄alkenyloxy- optionally substituted with Het¹² or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy-, hydroxy, halo, Het²-, —NR⁷R⁸, -carbonyl- NR⁹R¹⁰ or Het³-carbonyl-; R⁵ and R⁶ are each independently selected from hydrogen or C₁₋₄alkyl; R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl, Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl, Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-, Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-; R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-; R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl-optionally substituted with Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷, Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹⁴ and R¹⁵ are each independently selected from hydrogen, C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-; R¹⁶ represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; Het¹ represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het¹ is optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-, mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-; Het³, Het⁴ and Het⁸ each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or Het⁸ is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-, C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-; Het⁵ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁶ and Het⁷ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁹ and Het¹⁰ each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or amino-C₁₋₄alkyl-; Het¹¹ represents a heterocycle selected from indolyl or

Het¹² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het¹² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-; Het¹³ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁴ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁵ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁶ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C₁₋₄alkyl; and Het¹⁷ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl optionally substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl, aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.
 3. A compound according to claim 1 wherein; Z represents NH; Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO—, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO—, C₁₋₆alkyl-CO—C₁₋₆alkyl, —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—, —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—, —C₁₋₂alkyl-NR²¹—CH₂—CO—NH—C₁₋₃alkyl-, —NR²²—CO—C₁₋₃alkyl-NH—, —C₁₋₃alkyl-NH—CO-Het²⁰-, C₁₋₂alkyl-CO-Het²¹—CO—, or -Het²²-CH₂—CO—NH—C₁₋₃alkyl-; X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or —NR¹¹—C₁₋₂alkyl-; X² represents a direct bond, —C₁₋₂alkyl-, O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹² or NR¹²—C₁₋₂alkyl-; R¹ represents hydrogen, cyano, halo or hydroxy; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-, Ar⁵ or Het¹; R³ represents hydrogen; R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy- or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy- or Het²-; R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-; R¹³ represents hydrogen or Het¹⁴-C₁₋₄alkyl; R¹⁴ and R¹⁵ represent hydrogen; R¹⁶ represents hydrogen or C₁₋₄alkyl substituted with hydroxy; R¹⁷ represents hydrogen or C₁₋₄alkyl, in particular hydrogen or methyl; R¹⁸ represents hydrogen or C₁₋₄alkyl optionally substituted with hydroxy or phenyl; R¹⁹ represents hydrogen or C₁₋₄alkyl; R²⁰ represents hydrogen or C₁₋₄alkyl; R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or R²¹ represents mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C₁₋₄alkyloxy; R²² represents hydrogen or C₁₋₄alkyl optionally substituted with hydroxy or C₁₋₄alkyloxy; Het¹ represents thiazolyl optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het³ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het³ is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹⁶ represents a heterocycle selected from piperidinyl or pyrrolidinyl; Het²⁰ represents pyrrolidinyl, 2-pyrrolidinonyl, piperidinyl or hydroxy-pyrrolidinyl, preferably pyrrolidinyl or hydroxy-pyrrolidinyl; Het²¹ represents pyrrolidinyl or hydroxy-pyrrolidinyl; Het²² represents pyrrolidinyl, piperazinyl or piperidinyl.
 4. A compound according to claim 1 wherein; Z represents NH; Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO—, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO— or C₁₋₆alkyl-CO—C₁₋₆alkyl; X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or —NR¹¹—C₁₋₂alkyl-; X² represents a direct bond, O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹² or NR¹²—C₁₋₂alkyl-; R¹ represents hydrogen, cyano, halo or hydroxy, preferably halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₂₋₆alkynyl-, Ar⁵ or Het²-; R³ represents hydrogen; R⁴ represents hydroxy, C₁₋₄alkyloxy- or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy- or Het²-; R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-; R¹³ represents Het¹⁴-C₁₋₄alkyl; Het¹ represents thiazolyl optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het³ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het³ is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹⁶ represents a heterocycle selected from piperidinyl or pyrrolidinyl.
 5. A compound according to claim 1 wherein; Z represents NH; Y represents —C₃₋₉alkyl-, —CO—C₁₋₇alkyl- or —C₁₋₇alkyl-CO—; X¹ represents —NR¹¹—, —O— or —O—CH₂—; X² represents a direct bond, —O— or —O—CH₂—; R¹ represents halo; R² represents hydrogen, cyano, halo, hydroxy or C₂₋₆alkynyl-; R³ represents hydrogen; R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy- or Het²-; R¹² represents C₁₋₄alkyl or R¹² represents C₁₋₄alkyl-oxy-carbonyl; Het² represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C₁₋₄alkyl-; Het³ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het³ is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-.
 6. A compound according to claim 1 wherein; Z represents NH; Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₃₋₇alkyl-CO—NH optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-, —C₃₋₇alkenyl-CO—NH— optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino- or C₁₋₄alkyloxycarbonylamino-, C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₅alkyl-CO NR¹⁵—C₁₋₅alkyl-, —C₁₋₃alkyl-NH—CO-Het²⁰-, —C₁₋₂alkyl-CO-Het²¹-CO—, —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—, —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—, or —NR²²—CO—C₁₋₃alkyl-NH—; X¹ represents a direct bond, O or —O—C₁₋₂alkyl-; X² represents a direct bond, —CO—C₁₋₂alkyl-, NR¹², —NR¹²—C₁₋₂alkyl-, —O—N═CH— or —C₁₋₂alkyl-; R¹ represents hydrogen or halo; R² represents hydrogen or halo; R³ represents hydrogen; R⁴ represents hydrogen or C₁₋₄alkyloxy; R¹² represents hydrogen or C₁₋₄alkyl; R¹³ represents hydrogen or C₁₋₄alkyl; R¹⁴ represents hydrogen; R¹⁵ represents hydrogen; R¹⁶ and R¹⁷ each independently represent hydrogen or C₁₋₄alkyl; R¹⁸ and R¹⁹ each independently represent hydrogen or C₁₋₄alkyl optionally substituted with phenyl or hydroxy; R²⁰ and R²¹ each independently represent hydrogen or C₁₋₄alkyl optionally substituted with C₁₋₄alkyloxy; Het²⁰, Het²¹ and Het²² each independently represent a heterocycle selected from the group consisting pyrrolidinyl, 2-pyrrolidinonyl or piperidinyl optionally substituted with hydroxy.
 7. A compound according to formula (I) wherein said compound is selected from the group consisting of; 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine-12,15-dione, 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-13-(2-methylpropyl)-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,10,13]benzoxatriazacycloheptadecine-12,15-dione, 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-, 4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1-k][6,1,9,12]benzoxatriazacyclopentadecin-11(8H)-one, 19-chloro-18-fluoro-9,10,11a, 12,13,14,16,21-octahydro-22-methoxy-, 4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecine, 18-chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxy-14-methyl-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine, 19-chloro-8,9,10,11,12,13,14,15,16,21-decahydro-22-methoxy-15-methyl-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,9,12]benzoxatriazacyclopentadecine, 17-chloro-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl-, 12H-4,6-ethanediylidene-13,17-methanopyrimido[4,5-b][6,1,10,16]benzoxatriazacyclononadecin-12-one, 21-chloro-8,9,10,11,13,14,15,16,18,23-decahydro-25-methoxy-, 4,6-ethanediylidene-12H-pyrimido[4,5-b][6,1,10,13]benzoxatriazacyclohexadecin-12-one, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-13,14-dimethyl-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one, 19-chloro-15-ethyl-9,10,11,12,14,15,16,21-octahydro-22-methoxy-, or 4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecin-13(8H)-one, 19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxy-14,15-dimethyl-,
 8. A compound according to claim 1 wherein the X² substituent is at position 2′, the R¹ substituent is at position 4′, the R² substituent is at position 5′, the R³ substituent is at position 3 and the R⁴ substituent at position 7 of the structure of formula (I).
 9. (canceled)
 10. (canceled)
 11. (canceled)
 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective kinase inhibitory amount of a compound as described in claim
 1. 13. A process for preparing a compound as claimed in claim 1, comprising a) coupling the 6-acetoxy-quinazolines of formula (II) with the suitable substituted anilines of formula (III) to furnish the intermediates of formula (IV), and deprotecting the intermediates of formula (IV) followed by ring closure under suitable conditions.

b) Deprotecting the intermediates of formula (IV^(b)) followed by formation of the corresponding ether using the appropriate aminated alcohol under standard conditions provides the intermediates of formula (XXVIII). Next, deprotection followed by ring closure provides the target compounds of formula (I′^(b))


14. An intermediate of formula (III)

the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein V represents hydrogen or a protective group preferably selected from the group consisting of methylcarbonyl, t-butyl, methyl, ethyl, benzyl or trialkylsilyl; Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₃₋₇alkyl-CO—NH— optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-, —C₃₋₇alkenyl-CO—NH— optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—, —C₁₋₃alkyl-NH—CS-Het²⁰-, —C₁₋₃alkyl-NH—CO-Het²⁰-, C₁₋₂alkyl-CO-Het²¹-CO—, -Het²²-CH₂—CO—NH—C₁₋₃alkyl-, —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO—, —C₁₋₆alkyl-CO—C₁₋₆alkyl-, —CO-Het²⁰-, —C₁₋₂alkyl-NH—CO—CR¹⁶R¹⁷—NH—, —C₁₋₂alkyl-CO—NH—CR¹⁸R¹⁹—CO—, —C₁₋₂alkyl-CO—NR²⁰—C₁₋₃alkyl-CO—, —C₁₋₂alkyl-NR²¹—CH₂—CO—NH—C₁₋₃alkyl-, or —NR²²—CO—C₁₋₃alkyl-NH—; X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-; R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-, C₁₋₆alkyl-, halo-phenyl-carbonylamino-, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl, C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR⁵R⁶, C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C₁₋₄alkyl-oxy-; R⁵ and R⁶ are each independently selected from hydrogen or C₁₋₄alkyl; R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁸-C₁₋₄alkyl-, phenyl-C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷, C₂₋₄alkenylcarbonyl- optionally substituted with Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or R¹² represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹⁴ and R¹⁵ are each independently selected from hydrogen, C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-; R¹⁶ and R¹⁷ each indepedently represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R¹⁸ and R¹⁹ each indepedently represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R²⁰ and R²² each independently represents hydrogen or C₁₋₄alkyl optionally substituted with hydroxy or C₁₋₄alkyloxy; R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or R²¹ represents mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C₁₋₄alkyloxy; Het¹ represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het¹ is optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het¹³ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁴ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁵ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁶ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C₁₋₄alkyl; and Het¹⁷ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het²⁰, Het²¹ and Het²² each independently represent a heterocycle selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from hydroxy, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-; Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl optionally substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl, aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.
 15. (canceled)
 16. An intermediate of formula (XXX)

the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Y1 and Y2 each independently represent a C₁₋₅alkyl, C₁₋₆alkyl, CO—C₁₋₆alkyl, CO—C₁₋₅alkyl, Het²²-CH₂—CO, CO—CR¹⁶R¹⁶R¹⁷—NH—, Het²⁰, CR¹⁸R¹⁹—CO—CH₂—CO—NH—C₁₋₃alkyl-, —C₁₋₂alkyl-NR²¹—CH₂—CO— or CO—C₁₋₃alkyl-NH—; X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹¹, —NR¹¹—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-; X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹¹, —NR¹¹—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or —C₁₋₂alkyl-; R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-, C₁₋₆alkyl-, halo-phenyl-carbonylamino-, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl, C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR⁵R⁶, C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C₁₋₄alkyl-oxy-; R³ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one or more substituents selected from halo, C₁₋₄alkyloxy-, amino-, mono- or di(C₁₋₄alkyl)amino-, C₁₋₄alkyl-sulfonyl- or phenyl; R⁵ and R⁶ are each independently selected from hydrogen or C₁₋₄alkyl; R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl, Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl, Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-, Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-; R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-; R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl-optionally substituted with Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷, Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹⁶ and R¹⁷ each indepedently represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R¹⁸ and R¹⁹ each indepedently represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R²¹ represents hydrogen, C₁₋₄alkyl, Het²³-C₁₋₄alkylcarbonyl- or R²¹ represents mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C₁₋₄alkyloxy; R²³ represents Ar³, Ar⁴—C₁₋₄alkyl, C₁₋₄alkyl, C₂₋₆alkenyl optionally substituted with Het¹² or R¹⁷ represents C₁₋₄alkyl substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy, hydroxy, halo, Het², NR⁷R⁸, NR⁹R¹⁰-carbonyl or Het³-carbonyl; Het¹ represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het¹ is optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-, mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-; Het³, Het⁴ and Het⁸ each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or Het⁸ is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-, C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-; Het⁵ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁶ and Het⁷ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁹ and Het¹⁰ each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or amino-C₁₋₄alkyl-; Het¹¹ represents a heterocycle selected from indolyl or

Het¹² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het¹² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-; Het¹⁶ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C₁₋₄alkyl; and Het¹⁷ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het²⁰, Het²¹ and Het²² each independently represent a heterocycle selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from hydroxy, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-; Het²³ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Ar¹, Ar³, Ar⁴ and Ar⁵ each independently represent phenyl optionally substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl, aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.
 17. (canceled)
 18. (canceled)
 19. (canceled)
 20. An intermediate of formula (XXXIII)

the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein m represents 1, 2, 3 or 4; X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or C₁₋₂alkyl; Y₃ represents a C₁₋₅alkyl, CO—C₁₋₅alkyl or CO—CR¹⁶R¹⁷—NH— or C₁₋₅alkyl-CO-optionally substituted with amino, mono- or di(C₁₋₄alkyl)amino or C₁₋₄alkyloxycarbonylamino; R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-, C₁₋₆alkyl-, halo-phenyl-carbonylamino-, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl, C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR⁵R⁶, C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C₁₋₄alkyl-oxy-; R³ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one or more substituents selected from halo, C₁₋₄alkyloxy-, amino-, mono- or di(C₁₋₄alkyl)amino-, C₁₋₄alkyl-sulfonyl- or phenyl; R⁵ and R⁶ are each independently selected from hydrogen or C₁₋₄alkyl; R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁸-C₁₋₄alkyl-, phenyl-C₁₋₄alkyl-oxy-carbonyl-Het¹⁷, C₂₋₄alkenylcarbonyl- optionally substituted with Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹⁶ and R¹⁷ each indepedently represents hydrogen or C₁₋₄alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; Het¹ represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het¹ is optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het¹⁶ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C₁₋₄alkyl; Het]⁸ and Het¹⁹ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; and Ar¹ and Ar⁵ each independently represent phenyl optionally substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl, aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.
 21. (canceled)
 22. (canceled)
 23. (canceled) 